Implantable thermal treatment method and apparatus

ABSTRACT

A long-term implantable ultrasound therapy system and method is provided that provides directional, focused ultrasound to localized regions of tissue within body joints, such as spinal joints. An ultrasound emitter or transducer is delivered to a location within the body associated with the joint and heats the target region of tissue associated with the joint from the location. Such locations for ultrasound transducer placement may include for example in or around the intervertebral discs, or the bony structures such as vertebral bodies or posterior vertebral elements such as facet joints.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.13/792,001 filed on Mar. 9, 2013, incorporated herein by reference inits entirety, now abandoned, which is a continuation of U.S. patentapplication Ser. No. 12/898,401 filed on Oct. 5, 2010, now U.S. Pat. No.8,414,509, incorporated herein by reference in its entirety, which is adivision of U.S. patent application Ser. No. 10/351,450, filed on Jan.23, 2003, now U.S. Pat. No. 7,819,826, incorporated herein by referencein its entirety, which claims the benefit of U.S. provisional patentapplication Ser. No. 60/351,875 filed on Jan. 23, 2002, incorporatedherein by reference in its entirety, which claims the benefit of U.S.provisional patent application Ser. No. 60/351,827 filed on Jan. 23,2002, incorporated herein by reference in its entirety, which claims thebenefit of U.S. provisional patent application Ser. No. 60/410,603 filedon Sep. 12, 2002, incorporated herein by reference in its entirety, andwhich claims the benefit of U.S. provisional patent application Ser. No.60/411,401 filed on Sep. 16, 2002, incorporated herein by reference inits entirety. Priority is claimed to each of the foregoing applications.

This application is related to PCT International Application No.PCT/US2003/002211, filed on Jan. 23, 2003 and published as WO 03/061256A2 on Jul. 31, 2003, which publication is incorporated herein byreference in its entirety.

This application is also related to European Patent Application No.European Patent Office No. 03704007.8, which entered the national stageon Nov. 29, 2004 and was granted on Oct. 31, 2012 as EP Patent No.1503685, incorporated herein by reference in its entirety.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

Not Applicable

REFERENCE TO A COMPUTER PROGRAM APPENDIX

Not Applicable

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention is an implantable surgical device system andmethod for delivering therapeutic levels of energy to tissue in a livingbody. More specifically, it is a long-term implantable system and methodfor delivering therapeutic levels of ultrasound energy invasively withinthe body in order to treat chronic disorders associated with skeletaljoints. Still more specifically, it is a long-term implant system andmethod for delivering therapeutic ultrasound energy to spinal joints,such as in particular intervertebral discs or associated bony vertebralstructures.

2. Description of the Background Art

For many years, much research and commercial development has beendirected toward delivering energy to tissue in order to achieve variousdesired therapeutic results. Examples of energy modalities previouslydescribed for tissue treatment include: electrical current (both DC andAC, e.g. radiofrequency or “RF” current), plasma ion energy, sonicenergy (in particular ultrasound), light energy (e.g. laser, infrared or“IR”, or ultraviolet or “UV”), microwave induction, and thermal energy(e.g. convection or conduction). Other modalities for treating tissueinclude without limitation: cryotherapy (cooling tissue to desiredlevels to affect structure of function), and chemical therapy(delivering chemicals to the tissue to affect the tissue structure offunction). Each of these energy delivery and other treatment modalitieshas been extensively studied and characterized as providing uniquebenefits, as well as unique issues and concerns, with respect to tissuetherapy. Accordingly, many specific energy delivery methods and systemshave been disclosed to provide unique benefits for particular intendedtherapeutic applications.

Various specific tissue responses to energy delivery have also beenobserved and reported during the course of significant study andcharacterization. In one regard, tissues or their function may bedamaged by energy delivery such as thermal therapy. Examples ofpreviously disclosed, differentiated effects of thermal tissue therapygenerally characterized to damage tissue include, without limitation:ablation (which has been defined as either molecular dissociation or byachieving cellular necrosis), coagulation, degranulation, anddesiccation. Alternatively, energy delivery in certain particular formshas also been characterized as promoting reproductive stimulation incertain tissues. Certain desired results have been disclosed withrespect to intending controlled tissue damage with tissue thermaltherapy; other desired results have been disclosed with respect topromoting tissue reproduction with tissue thermal therapy. In any event,because of the pronounced effects observed from tissue energy delivery,it is often desired to control and accurately select the localization oftissue/energy interaction in order to treat only the intended tissue,else normal surrounding tissue is effected with harmful results.

Accordingly, the different energy delivery modalities have beenspecifically characterized as providing particular benefits and problemsversus other modalities with respect to various specific tissues andrelated medical conditions. Examples of specific medical conditions andrelated tissue that have been studied and characterized for tissueenergy delivery include: tumors such as cancer (e.g. liver, prostate,etc.); vascular aneurysms, malformations, occlusions, and shunts;cardiac arrhythmias; eye disorders; epidermal scarring; wrinkling; andmusculo-skeletal injury repair. The nature of the condition to betreated, as well as the anatomy of the area, can have significant impacton the desired result of energy delivery, which directly differentiatesbetween the appropriateness or inappropriateness of each of thedifferent energy delivery modalities for such application (as well asthe corresponding particular operating parameters, systems, and methodsfor delivering such energy).

Depending upon the particular energy modality, various differentparameters may be altered to affect the thermal effect in particulartissues, including which type of effect is achieved (e.g. ablation,coagulation, desiccation, etc.), as well as depth or degree of theeffect in surrounding tissues. For the purpose of a generalunderstanding, however, known tissue responses to thermal therapies,e.g. effect of changing temperatures to particular levels, have beenpreviously characterized for certain tissues in prior disclosures whichare summarized as follows.

As described above, temperature elevation of biological tissues iscurrently used for outright tissue destruction or to modify tissues toenhance other therapies. Low temperature elevations (41-45° C.) ofrelatively short duration (<30-60 min) have been disclosed as beingassociated with cell damage, but generally only to such extent to berepairable and considered non-lethal. In this range, it is believed thatheat mediated physiological effects include heat induced acceleration ofmetabolism or cellular activity, thermal inactivation of enzymes,rupture of cell membranes, and delayed onset of increasing blood flowand vessel permeability. Prior disclosures addressing temperatureexposures in excess of 45° C. and/or longer durations have stated thatcellular repair mechanisms no longer function due to denaturation of keyproteins or can't keep up with the accumulating damage. According tothermal therapy at such temperatures, complete cell death and necrosishave been observed in certain particular tissues to be fully expressedin approximately 3-5 days. Temperature exposures in the 42-45° C.regimen are commonly used for example as an adjuvant to radiation cancertherapy and chemotherapy, and have been considered for enhancing genetherapy and immunotherapy as well. Higher temperature elevations (50+°C.) have been investigated for inducing desirable physical changes intissue, ranging from applications such as controlled thermal coagulationfor “tightening” ligaments and joint capsules, tissue reshaping, andselective tissue thermal coagulation for destroying cancerous and benigntumors. High temperature exposures (50+° C.) are generally believed toproduce rather lethal and immediate irreversible denaturation andconformational changes in cellular and structural proteins in varioustissues, thereby thermally coagulating such tissues.

In general, heat-induced cell damage or tissue structural changesdescribed above are believed to be attributed to thermal denaturationand aggregation of key protein structures. The accumulation of thisthermal damage can be modeled using the Arrhenius rate process equation,which establishes a relationship between rate of thermal damage and theduration and temperature of exposure:

$\begin{matrix}{{\frac{1}{\tau} = {A \cdot {\mathbb{e}}^{{- \Delta}\;{E/{RT}}}}},} & (1)\end{matrix}$where ΔE is activation energy (J mol⁻¹), R is the universal gas constant(8.32 J mol⁻¹K⁻¹), A is the rate constant (s⁻¹), T is temperature inKelvin, and 1/τ is rate of thermal damage (s⁻¹). Using this expression(Eqn. 1), a relationship can be derived to determine an exposure time(τ₂) and/or temperature elevation (T₂) required to produce an equivalentobserved biological effect associated with a specified temperature (T₁)and time exposure (τ₁). This is the basis of the thermal iso-effectequation as shown below, which is non-linear with respect to temperatureexposure and linear with respect to exposure time:τ₂=τ₁ e ^((ΔE/RT) ¹ ^(T) ² ^()(T) ¹ ^(-T) ² ⁾=τ₁K^((T) ¹ ^(-T) ² ⁾,  (2)where the parameter K is approximated as constant for typicaltherapeutic temperature elevations (10-30° C.). Furthermore, extensivein vitro and in vivo studies have demonstrated that ΔE for thermaldamage is approximately constant at 140 J mol⁻¹ for temperatures greaterthan 43° C. Thus, the relationship between time and temperature for agiven biological effect depends upon activation energy only. Thus, asdetermined from the hyperthermia biology literature, K≅2 for T≧43° C.and K≅4-6 for T<43° C. The different values split at approximately 43°C. in order to model the biphasic behavior in the rate response, withfaster damage accumulation after a break around 43° C. These values holdfor lethal cellular damage, but not coagulation of structural proteins(collagen). Traditionally this iso-effect dose has been used tocharacterize hyperthermia cancer treatments with a target temperatureelevation of 42.5-45° C., and has led to 43° C. becoming the historicalreference dose temperature. This forms the basis of the thermaliso-effect dose (TID) equation, which as shown below can be used tocalculate thermal dose of a varying temperature exposure over time as anequivalent exposure duration at 43° C. (or other reference temperature).Temperature time history is equated to a thermal dose at a knowntemperature reference.

$\begin{matrix}{{{EM}_{43} = {{\int_{0}^{t_{f}}{K^{({T - 43})}{\mathbb{d}t}}} = {\sum\limits_{t = 0}^{t_{final}}{\Delta\;{tK}^{({T - 43})}}}}},} & (3)\end{matrix}$where dt is a time step (min) and EM₄₃ is thermal dose expressed inequivalent minutes at 43° C.

Various previously published disclosures have verified the Arrheniusmodel and the iso-effect relationship of different temperature-timeexposures for generating trans-epidermal thermal necrosis in skin.Applying the TID analysis, a threshold of approximately 320 EM₄₃(wherein “EM” represents “equivalent minutes” at the given temperatureshown in subscript) as found for temperatures between 44-60° C. Thermaldosages between 10-100 EM₄₃ have been shown to correlate with improvedresponse to hyperthermia and radiation therapy. For a conservativeapproach 250 EM_(43° C.) is a threshold dose for complete thermalnecrosis, where reported values range from 25-240 EM43° C. for brain andmuscle tissue, respectively.

In addition, thermal coagulation or coagulation necrosis have beendisclosed to occur in tissues exposed to temperatures greater thanapproximately 55° C. for a duration of minutes, in particular respect tocollagen in certain structures studied. Thermal coagulation of softtissues generally takes place only for temperatures in excess of 50° C.Numerous investigators have validated the “TID” (or “temperatureiso-dose”) concept for predicting lesions using 240-340 EM 43° C. as athreshold dose and critical temperatures of 53-54° C. for coagulatingmuscle.

Therapeutic Energy Delivery for Spinal Disorders

Spinal disorders have been the topic of significant study and commercialdevelopment for therapeutic energy delivery. In particular, variousspecific conditions that have been studied with respect to particularmodes of therapeutic energy delivery.

Of particular interest has been chronic lower back pain. Chronic lowback pain is a significant health and economic problem in the UnitedStates, being the most costly form of disability in the industrialsetting. For a substantial number of these patients the intervertebraldisc is considered the principal pain generator. Traditionally, patientswho fail conservative therapy have few treatment options besidediscectomy or fusion, either of which can result in significantmorbidity and variable outcomes. Recent efforts have been directedtoward investigating thermal therapy for providing a healing effect oncollagenous tissues, and therefore this modality has been incorporatedinto several minimally invasive back pain treatments.

Early orthopedic use of high temperature heat therapy was to manageshoulder instability. In this application, the shoulder capsule istreated with laser or radio-frequency (RF) thermal energy totemperatures typically in the range of 70 to 80° C. This treatment hasbeen disclosed to stabilize the joint by inducing tissue contraction.Such treatment also has been disclosed to result in an acute decrease instiffness (e.g. as much as 50%) that may be recovered due to biologicremodeling. However, the long-term benefits of this treatment have beenquestioned since the collagenous tissue may re-lengthen over time.

The contraction associated with thermal therapy, which can reach as highas 50% along the fiber direction in the shoulder capsule, has beencorrelated with thermal denaturation. Thermal denaturation is anendothermic process in which the collagen triple helix unwinds after acritical activation energy is reached. Differential scanning calorimetry(DSC) is a technique to measure both the denaturation temperature(T_(m)—the peak temperature corresponding to this critical activationenergy) and the total enthalpy of denaturation (ΔH—the total energyrequired to fully denature the collagen). This technique can be used tocorrelate thermal exposure with the resulting degree of denaturation fora specific collagenous tissue, and thus to guide the development of anoptimal thermal dose.

Intradiscal electrothermal therapy (IDET) has been recently introducedas a minimally invasive, non-operative therapy in which a temperatureelevation is applied in order to treat discogenic low back pain. In thisprocedure, a temporary catheter containing a 5 cm long resistive-wireheating coil is introduced percutaneously into the disc underfluoroscopic guidance. The internal temperature of the device is thenraised from 65° C. to 90° C. over a course of 16 minutes. This procedureis intended to produce temperatures sufficient to contract annularcollagen and ablate annular nociceptors. A controlled, 12 month trial ofIDET on a relatively small patient population (36 individuals)demonstrated some relief of back pain in 60% of patients and totalrelief in 23%. A two-year follow-up study of 58 patients was disclosedto result in clinically significant improvement in pain, physicalfunction, and quality of life. While these results have been consideredby some to be promising, prospective placebo-controlled trials arelacking, and the therapeutic mechanisms of thermal therapy are unknown.Proposed therapeutic mechanisms of such technique have included: 1)collagen denaturation, causing annular stiffening, and tissueremodeling; 2) annular de-innervation; and 3) ablation ofcytokine-producing cells. Due to mechanistic uncertainty, treatmentoptimization and patient selection are generally empirically based.

The effect of heat on collagen denaturation and biomechanical propertieshas been investigated in various tissues: knee and shoulder capsule,tendon, and chordae tendineae. In general, at least one prior disclosurereports that significant denaturation and shrinkage occurred in tissuetreated at 65° C. and above for 1-5 minutes. However, given that theannular architecture of intervertebral discs is quite different fromthese other tissues it is has not been previously made clear that priorresults can be directly extrapolated to the intervertebral disc.

Further more detailed background information related to various aspectsof thermal tissue therapy and/or chronic back pain is variouslydisclosed in the following publications: Amonoo-Kuofi, H. S., 1991,“Morphometric changes in the heights and anteroposterior diameters ofthe lumbar intervertebral discs with age.” J Anat 159-68;

Arnoczky, S. P. and Aksan, A., 2001, “Thermal modification of connectivetissues: basic science considerations and clinical implications.” InstrCourse Lect 3-11; Chen, S. S., Wright, N. T. and Humphrey, J. D., 1997,“Heat-induced changes in the mechanics of a collagenous tissue:isothermal free shrinkage.” J Biomech Eng 4, 372-8; Chen, S. S., Wright,N. T. and Humphrey, J. D., 1998, “Heat-induced changes in the mechanicsof a collagenous tissue: isothermal, isotonic shrinkage.” J Biomech Eng3, 382-8; Dewey, W. C., 1994, “Arrhenius relationships from the moleculeand cell to the clinic.” Int J Hyperthermia 4, 457-83; Flandin, F.,Buffevant, C. and Herbage, D., 1984, “A differential scanningcalorimetry analysis of the age-related changes in the thermal stabilityof rat skin collagen.” Biochim Biophys Acta 2, 205-11; Gerber, A. andWarner, J. J., 2002, “Thermal capsulorrhaphy to treat shoulderinstability.” Clin Orthop 400, 105-16; Hall, B. K., 1986, “The role ofmovement and tissue interactions in the development and growth of boneand secondary cartilage in the clavicle of the embryonic chick.” JEmbryol Exp Morphol 133-52; Hayashi, K. and Markel, M. D., 2001,“Thermal capsulorrhaphy treatment of shoulder instability: basicscience.” Clin Orthop 390, 59-72; Hayashi, K., et al., 2000, “Themechanism of joint capsule thermal modification in an in-vitro sheepmodel.” Clin Orthop 370, 236-49; Hayashi, K., et al., 1997, “The effectof thermal heating on the length and histologic properties of theglenohumeral joint capsule.” Am J Sports Med 1, 107-12; Heary, R. F.,2001, “Intradiscal electrothermal annuloplasty: the IDET procedure.” JSpinal Disord 4, 353-60; Hecht, P., et al., 1999, “Monopolarradiofrequency energy effects on joint capsular tissue: potentialtreatment for joint instability. An in vivo mechanical, morphological,and biochemical study using an ovine model.” Am J Sports Med 6, 761-71;Karasek, M. and Bogduk, N., 2000, “Twelve-month follow-up of acontrolled trial of intradiscal thermal anuloplasty for back pain due tointernal disc disruption.” Spine 20, 2601-7; Kronick, P., et al., 1988,“The locations of collagens with different thermal stabilities infibrils of bovine reticular dermis.” Connect Tissue Res 2, 123-34; LeLous, M., et al. 1982. “Influence of collagen denaturation on thechemorheological properties of skin, assessed by differential scanningcalorimetry and hydrothermal isometric tension measurement.” BiochimBiophys Acta 2, 295-300; Lopez, M. J., et al., 2000, “Effects ofmonopolar radiofrequency energy on ovine joint capsular mechanicalproperties.” Clin Orthop 374, 286-97; Miles, C. A. and Ghelashvili, M.1999, “Polymer-in-a-box mechanism for the thermal stabilization ofcollagen molecules in fibers.” Biophys J 6, 3243-52; Naseef, G. S., etal., 1997, “The thermal properties of bovine joint capsule. The basicscience of laser- and radiofrequency-induced capsular shrinkage.” Am JSports Med 5, 670-4; Nieminen, M. T., et al., 2000, “Quantitative MRmicroscopy of enzymatically degraded articular cartilage.” Magn ResonMed 5, 676-81; (Nrc/Im), N. R. C. A. I. O. M. (2001). “MusculoskeletalDisorders and the workplace: low back and upper extremities.” WashingtonD.C., National Academy Press; Saal, J. A. and Saal, J. S., 2002,“Intradiscal electrothermal treatment for chronic discogenic low backpain: prospective outcome study with a minimum 2-year follow-up.” Spine9, 966-73; discussion 973-4; Saal, J. S. and Saal, J. A., 2000,“Management of chronic discogenic low back pain with a thermalintradiscal catheter. A preliminary report.” Spine 3, 382-8; Schachar,R. A., 1991, “Radial thermokeratoplasty. Int Ophthalmol” Clin 1, 47-57;Schaefer, S. L., et al., 1997, “Tissue shrinkage with theholmium:yttrium aluminum garnet laser. A postoperative assessment oftissue length, stiffness, and structure.” Am J Sports Med 6, 841-8;Schwarzer, A. C., et al., 1995, “The prevalence and clinical features ofinternal disc disruption in patients with chronic low back pain.” Spine17, 1878-83; Urban, J. P. and Mcmullin, J. F., 1985, “Swelling pressureof the intervertebral disc: influence of proteoglycan and collagencontents.” Biorheology 2, 145-57; Vangsness, C. T., Jr., et al., 1997,“Collagen shortening. An experimental approach with heat.” Clin Orthop337, 267-71; Vujaskovic, Z., et al., 1994, “Effects of intraoperativehyperthermia on peripheral nerves: neurological and electrophysiologicalstudies.” Int J Hyperthermia 1, 41-9; Wallace, A. L., et al., 2000, “Thescientific basis of thermal capsular shrinkage.” J Shoulder Elbow Surg4, 354-60; and Wallace, A. L., et al., 2002, “Creep behavior of a rabbitmodel of ligament laxity after electrothermal shrinkage in vivo.” Am JSports Med 1, 98-102. The disclosures of these references are hereinincorporated in their entirety by reference thereto.

Chronic lower back pain (e.g. discogenic lumbar pain) and related motornerve deficit is typically due to damaged or herniated vertebral discswhich either directly impinge on surrounding nerves or cause irritatinginflammation. Traditional treatment options include surgery,anti-inflammatory drugs, physical therapy, etc., with surgery typicallythe last option. Due to difficulty of surgical procedure, complicationsand time of recovery, alternative procedures have been investigated.Recently, intradiscal thermal therapy has been introduced as aminimally-invasive alternative in the treatment of various spinaldisorders such as chronic low back pain and otherwise disorders relatedto intervertebral disc abnormalities.

In particular, several different systems and methods have been disclosedfor treating various abnormal conditions associated with intervertebraldiscs specifically by delivering electrical current in the RF rangeduring invasive treatment procedures in and around the disc within thebody. Other previously disclosed examples intended to invasively delivertherapeutic levels of energy in order to treat various spinal disordersinclude delivery of plasma ion energy (e.g. CoblationR from Arthrocare,Inc.), laser light energy, or thermal energy from conductive heatingelements (e.g. the SpineCATH DEC procedure, commercially available fromOratec Interventions, introduced above). At least one other priordisclosure is intended to deliver heated thermoplastic material to allowit to flow into and then set upon cooling within the nucleus of anintervertebral disc in order to replace the nucleus pulposus.

Further more detailed examples of energy delivery systems and methodssuch as of the types just described, that are intended to provideinvasive therapy to treat various conditions associated withintervertebral disc disorders are variously disclosed in the followingissued U.S. Patents: U.S. Pat. No. 4,959,063 to Kojima; U.S. Pat. No.6,264,650 to Hovda et al.; U.S. Pat. No. 6,264,659 to Ross et al.Examples are also disclosed in the following published U.S. patentapplication: US 2001/0029370 to Hodva et al., now U.S. Pat. No.6,464,695. Other examples are disclosed in the following publishedinternational patent applications: WO 00/49978 to Guagliano et al.; WO00/71043 to Hovda et al.; WO 01/26570 to Alleyne et al. Additionaldisclosure is provided in the following published reference: Diederich CJ, Nau W H, Kleinstueck F, Lotz J, Bradford D (2001) “IDTT Therapy inCadaveric Lumbar Spine: Temperature and thermal dose distributions,Thermal Treatment of Tissue: Energy Delivery and Assessment,” Thomas P.Ryan, Editor, Proceedings of SPIE Vol. 4247:104-108. The disclosures ofall these references provided in this paragraph are herein incorporatedin their entirety by reference thereto.

Ultrasound energy delivery and the effects of such energy on variousdifferent tissue structures has been the topic of significant recentstudy. The particular benefits of ultrasound delivery have beensubstantially well characterized, in particular with respect todifferent types of tissues as well as different ultrasound energydeposition modes. Many different medical device systems and methods havebeen disclosed for delivering therapeutic levels of ultrasound totissues to treat wide varieties of disorders, including for examplearterial blockages, cardiac arrhythmias, and cancerous tumors. Suchdisclosures generally intend to “ablate” targeted tissues in order toachieve a desired result associated with such particular conditions,wherein the desired response in the particular tissues, and theultrasound delivery systems and methods of operation necessary for thecorresponding energy deposition modalities, may vary substantiallybetween specific such “ultrasound ablation” systems and methods.

Further more detailed examples of ultrasound delivery systems andmethods such as of the type just described are disclosed in thefollowing issued U.S. patents which are incorporated herein byreference: U.S. Pat. No. 5,295,484 to Marcus et al.; U.S. Pat. No.5,620,479 to Diederich; U.S. Pat. No. 5,630,837 to Crowley; U.S. Pat.No. 5,733,280 to Sherman et al.; U.S. Pat. No. 6,012,457 to Lesh; U.S.Pat. No. 6,024,740 to Lesh et al.; U.S. Pat. No. 6,117,101 to Diederichet al.; U.S. Pat. No. 6,164,283 to Lesh; U.S. Pat. No. 6,245,064 to Leshet al.; U.S. Pat. No. 6,254,599 to Lesh et al.; and U.S. Pat. No.6,305,378 to Lesh et al. Other examples are disclosed in the followingpublished foreign patent applications which are incorporated herein byreference: WO 00/56237 to Maguire et al.; WO 00/67648 to Maguire et al.;WO 00/67656 to Maguire et al.; WO 99/44519 to Langberg et al.

In addition, ultrasound enhanced drug delivery into tissues, e.g. toincrease dispersion, permeability, or cellular uptake of therapeuticcompounds such as drugs, has been well characterized and disclosed inmany different specific forms.

Further more detailed examples of ultrasound energy delivery systems andmethods such as those just described are disclosed in the following U.S.Patent References: U.S. Pat. No. 5,725,494 to Brisken; U.S. Pat. No.5,728,062 to Brisken; U.S. Pat. No. 5,735,811 to Brisken; U.S. Pat. No.5,846,218 to Brisken et al.; U.S. Pat. No. 5,931,805 to Brisken; U.S.Pat. No. 5,997,497 to Nita et al.; U.S. Pat. No. 6,210,393 to Brisken;U.S. Pat. No. 6,221,038 to Brisken; U.S. Pat. No. 6,228,046 to Brisken;U.S. Pat. No. 6,287,272 to Brisken et al.; and U.S. Pat. No. 6,296,619to Brisken et al. The disclosures of these references are hereinincorporated in their entirety by reference thereto.

Additional previously disclosed examples for ultrasound energy deliverysystems and methods are intended to treat disorders associated with thespine in general, and in some regards of the intervertebral disc inparticular. However, these disclosed systems are generally adapted totreat such disorders chronically from outside of the body, such as forexample via transducers coupled to a brace worn externally by a patient.Therefore locally densified US energy is not achieved selectively withinthe tissues associated with such disorders invasively within the body.At least one further disclosure, however, proposes delivering focusedultrasound energy from outside the body for the intended purpose oftreating intervertebral disc disorders, in particular with respect todegenerating the nucleus pulposus to reduce the pressure within the discand thus onto the adjacent spinal cord. However, the ability to actuallyachieve such targeted energy delivery at highly localized tissue regionsassociated with such discs, and to accurately control tissue temperatureto achieve desired results, without substantially affecting surroundingtissues has not been yet confirmed or taught.

Further more detailed examples of such systems and methods intended totreat spinal disorders with ultrasound energy from outside of the bodyare variously disclosed in the following issued U.S. Patents: U.S. Pat.No. 5,762,616 to Talish; U.S. Pat. No. 6,254,553 to Lidgren et al. Otherexamples are disclosed in the following published international patentapplications: WO 97/33649 to Talish; WO 99/19025 to Urgovich et al.; andWO 99/48621 to Cornejo et al. The disclosures of these references areherein incorporated in their entirety by reference thereto.

Exposure of soft and hard tissue, including the spine and joints, tovaried degrees of heat or other energy delivery can provide variedtherapeutic effects. For example, heat at high temperatures and thermaldoses can shrink tissues, change the structural matrix, and generatephysiological changes and/or kill cells. Heat at low temperatures andcan generate permeability changes or changes in the cellulartransport/metabolism that increase effectiveness or deposition ofcertain pharmaceutical agents.

Heat can be provided using ultrasound (US), radio frequency (RF), laser,and the like, using invasive or non-invasive application techniques. Forexample, in order to treat internally embedded sensitized nerves orcells making inflammatory factors, invasive techniques are preferred sothat the heat source can be placed in close proximity to the targettissue. This can be accomplished using conventional surgical techniques,where the patient is opened, and a heat source is inserted directly(e.g., using a directly implantable device such as described in U.S.Pat. No. 5,620,497, incorporated herein by reference), or indirectlythrough a catheter or other delivery device. When the procedure iscomplete, the heat source is removed and the patient is closed.

However, despite the many benefits of temporary devices and theiracutely delivered treatments, a single treatment or a contemporaneousseries of discrete treatments in those previous examples may not provideadequate results in many cases. In one regard, the ability to treat manychronic ailments is limited in the setting of an acute invasion into thebody required by temporary devices. Therefore, it may be necessary torepeat the treatment at a later date if a single application is notsufficient for the ailment. Accordingly, longer term implantable devicesand treatments are preferred for many medical therapies.

In this regard, the term “temporary” as herein used to describe certainmedical devices, systems, or methods, including with respect toimplants, is intended to mean adapted for acute use, such as in ahospital or outpatient surgical room or suite, over a relatively shortperiod of time. In general, patients do not carry temporary devicesimplanted within them away from a healthcare facility—they are used inan acute setting typically accompanied by observation by healthcarepersonnel (e.g. such observation by a healthcare provided may be eithercontinuous, or for longer temporary treatments may be sporadic, or maysimply initiate a procedure via an implant and return to remove it aftera time specified or an endpoint parameter is met). The time period bywhich temporary medical devices are typically left indwelling within thebody is usually on the order of minutes, or possibly hours, though insome extreme cases some temporary medical devices can be left indwellingfor as much as 1-5 days (though again typically under professional care,such as during a hospital stay). Temporary medical devices also ofteninclude portions of the device extending externally of the patient'sbody, such as for example catheters or leads that interface with othercooperating hardware such as actuators or diagnostic systems.

In contrast, the terms “permanent implant” are herein intended to mean amedical device implant that is intended for long-term implantation forchronic therapy or use. In such cases, patient's carry such implantindwelling within their bodies during their daily lives. Typically,these permanent implants are intended for indefinite periods andassociated with chronic conditions ameliorated or diminished by thepermanent implant, but typically not cured upon removal of the permanentimplant. As such, they are not generally intended to be removed, thoughoften may require removal, such as for replacement due to limitation ofthe lifespan of the implant itself, or for example changing condition ofthe patient. Such changing conditions may include, for example andwithout limitation: growth with respect to pediatric patients, otherchanges in physique, changes in condition being treated or otherwisewith respect to the environment and/or needs underlying the implant'spresence.)

The terms “semi-permanent implant” are herein intended to mean implantsthat are intended for implantation over a period that lasts longer thanconsidered under an “acute” setting, e.g. longer than typically providedfor under the care of a healthcare provider and longer than most“temporary” medical devices such as temporary implants, though usuallyover a shorter period than most “permanent implants”. Semi-permanentimplants are typically carried indwelling within the patient away fromthe healthcare facility and out from under the direct observation of aprofessional caregiver. They most usually remain indwelling during thepatient's daily living for a period of days, possibly weeks, andpossibly in some cases even years. These implants are generally intendedto be carried within the patient for a limited period of time, however,and then to be removed.

Moreover, the terms “long-term” where herein used to describe animplantable device, or related system or procedure, include bothpermanent and semi-permanent implants unless otherwise specificallyindicated or would be otherwise readily apparent to one of ordinaryskill. Moreover, the use of the terms “permanent implant” generallycontemplate similar application with respect to “semi-permanentimplants” unless otherwise specifically indicated or readily apparent tobe exclusive to one of ordinary skill.

Various medical device systems and methods have been disclosed relatedto chronic treatment of various medical disorders by delivering energyto tissue from permanent or semi-permanent implants. Many such priordisclosures relate specifically to providing implantable electricalenergy delivery devices, and in particular relation to spinal cordstimulation. Many of such devices are intended to be long-term implants.

One example of a disclosed method of using a spinal cord stimulationlead involves implanting the lead in the epidural space and includes anelongate lead paddle located at the distal end of the lead. An array ofelectrodes is located on the lead paddle. The array has at least threecolumns of electrodes and includes a column having at least oneelectrode positioned substantially over the midline of the lead paddle,a column of at least one electrode positioned laterally of the midlineon one side thereof, and a column of at least one electrode positionedlaterally of the midline on the other side thereof. At least one of thecolumns within the array has more than one electrode. Each of theelectrodes is interconnected by a conductor to a respective terminal atthe proximal end of the lead. The lead is implanted such that themidline of the lead paddle is positioned over the midline of the spinalcord. Each electrode is independently selectable such that the spinalcord may be stimulated unilaterally or bilaterally.

Another example of an apparatus for multi-channel transverse epiduralspinal cord stimulation uses a multi-channel pulse generator driving aplurality of electrodes mounted near the distal end of a lead. Theseelectrodes are mounted in one or more lines, generally perpendicular toa lead axis, and having a planar surface along one surface of the lead.The lead is implanted adjacent to the spinal cord dura mater with theelectrodes transverse and facing the spinal cord. Pulses generated bythe pulse generator for each channel are normally simultaneous, of equalamplitude and of equal duration, however the pulse generator is arrangedsuch that pulses for each channel can selectably alternate in time, canselectably be of unequal amplitude, or both. The changes in pulse timingand magnitude permit shifting the electrical stimulation field and theresulting paresthesia pattern after installation to accommodate improperlead placement or postoperative dislocation and to minimize unwantedmotor responses.

A wide variety of spinal stimulation energy delivery systems and methodshave been disclosed, generally with respect to providing electricalcurrent to cause a nervous stimulation to produces a change in someinnervated bodily function. For example, at least one disclosureinvolves an apparatus providing timed electrical stimulus pulses in thefluid of the sacral canal to conduct electrical stimulus to the spinalcord to stimulate miturition and certain muscles in paraplegic mammals,e.g. to evacuate the bladder.

In another example, a method for electrical spinal cord stimulation wasdisclosed for treating orgasmic dysfunction. Stimulating electrodes areplaced in the spinal canal via a needle inserted between the appropriatevertebrae in parallel with the spinal cord. The electrodes are connectedto a power source. Through variable transmission of electrical signals apatient suffering from orgasmic dysfunction may once again achieveorgasm.

Long-term, electrical spinal cord stimulation has been widelyinvestigated for treating various types of pain, such as back pain inparticular, as well as other types of pain such as angina.

According to at least one example, a facet joint pain relief method andapparatus is disclosed that depolarizes the medial branch of the spinalnerve associated with a painful facet joint so as to block pain impulsesfrom reaching the spinal cord. The preferred apparatus includes aneurostimulator and two or more electrodes which carry electrical pulsesto the target nerve or nerves. The impulses are intense enough to causedepolarization of a given medial branch and its articular branches, butnot so large as to cause depolarization of the spinal cord itself. Thestimulator in one regard is physically small and battery operated,facilitating implantation underneath the skin. The stimulator includes acontroller and appropriate electronics operative to generate electricalimpulses tailored to an individual's need for appropriate pain relief interms of pulse frequency, pulse width, and pulse amplitude. In analternative embodiment, the stimulator further includes electrodes andelectrical circuitry operative to monitor myoelectrical activitygenerated by the surrounding muscles and modulate the impulses generatedby the stimulator to meet the demands of the individual's activityand/or prolong battery life.

Another example provides a method and apparatus for providing feedbackto spinal cord stimulation for angina treatment. Techniques for cardiacmonitoring and angina pectoris treatment using a cardiac conditiondetector and stimulating electrode are disclosed. The detector andelectrode are implanted, and angina is relieved by transmittingelectrical pulses to the stimulating electrode while the patient isgiving an indication of an ischemic event that otherwise would beindicated by the angina.

A variety of mechanisms have been previously disclosed that are intendedto provide paths to and into bony structures of the spine for deliveringa spinal implant there. Many disclosures have intended to addressmaintaining position of electrodes during electrical coupling to tissue.Several disclosures provide techniques intended for implanting a leadwith therapy delivery elements, such as electrodes or drug deliveryports, within vertebral or cranial bone so as to maintain those elementsin a fixed position relative to a desired treatment site. Additionaltechniques have been intended for non-invasively positioning andre-positioning the therapy delivery elements after implantation intosuch bone cavities. Further technique is disclosed using a positioncontrol mechanism and/or a position controller for adjusting in situ theposition of the therapy delivery elements relative to the targetedtissue. The therapy delivery elements may be positioned laterally in anydirection relative to the target, or toward or away from the treatmentsite. These techniques have been particularly intended for use withelectrical stimulation or drug infusion to the targeted tissue.

Another disclosure provides an apparatus for providing a therapy in orthrough one or more trans-sacral axial instrumentation/fusion (TASIF)bore through vertebral bodies in general alignment with visualized,anterior or posterior axial instrumentation/fusion line (AAIFL or PAIFL)in a minimally invasive, low trauma manner and providing a therapy tothe spine employing the trans-sacral axial bore. Anterior or posteriorstarting positions aligned with the AAIFL or PAIFL are accessed throughrespective anterior and posterior tracts. Curved or relatively straightanterior and curved posterior TASIF bores are formed from the anteriorand posterior starting positions. The therapies performed through theTASIF bores include ductoscopy, full and partial discectomy,vertebroplasty, balloon-assisted vertebroplasty, drug delivery,electrical stimulation and various forms of spinal disc cavityaugmentation, spinal disc replacement, fusion of spinal motion segments,and radioactive seeds implantation. Axial spinal implants and bonegrowth materials can also be placed in the TASIF bores.

Various disclosures have also been intended to provide feedback controlfor either adjusting the positioning of therapy delivery elements orother aspects of therapy, and in particular relation to spine therapydelivery elements.

In one group of examples, an apparatus and technique for electricalstimulation of the central or peripheral nervous system based uponchanges in the position of a patient is disclosed. A position sensor ischronically implanted in the patient, such as in one specific example amercury switch position sensor which indicates whether a patient iserect or supine. This position information is used by a chronicallyimplanted pulse generator to vary the stimulation intensity. Theintensity may be controlled by changes in pulse amplitude, pulse width,number of pulses per second, burst frequency, number of pulses perburst, electrode polarity, or other convenient parameter whichaccomplishes the particular medical purpose within an application. Theoutput of the chronically implanted pulse generator is applied to thespinal cord, peripheral nerves, and/or targets in the brain with leadsand electrodes in a manner consistent with the given medical need. Suchstimulation is useful in the treatment of chronic intractable pain,hemodynamic insufficiency resulting in angina, peripheral vasculardisease, cerebral vascular disease, various movement disorders, andbowel and bladder control.

Another example is directed toward living tissue stimulation andrecording techniques with local control of active sites. Implantableelectrodes are adapted to interact with electrically excitable tissue byan implantable, programmable controller that receives power from a maincable and data from a data conductor that identifies the stimulation andrecording electrodes to be activated. The implantable controller enableselectrical signals to be transmitted between a distal site of powergeneration and a selected subset of multiple electrodes with a minimumnumber of conductor wires.

Long-term electrical stimulus, such as via long-term implants, has alsobeen investigated for promoting bone growth, in particular relation tothe spine, as follows.

According to one general example, two electrodes are implanted into thetissue near the base site for bone growth. The electrodes are coupled toa bone growth stimulator which generates an alternating current thatstimulates bone growth. Other examples using electrical stimulus topromote bone growth abound, in particular with respect to bonystructures and implants related to the spine.

In one additional example, an implantable growth tissue stimulator andmethod is disclosed with a hand-held programmer/monitor for programmingand monitoring an implantable tissue growth stimulator. The stimulatorincludes circuitry for implementing selected operations in response to adown-link signal transmitted by the programmer/monitor, various circuitssuch as control circuit and transmit/receive circuit is used fortransmitting up-link and down-link signals to and from the implantablebone growth stimulator.

According to another example a preformed extendable mesh cathode for animplantable bone growth stimulator has been disclosed. An electricalsignal generator is provided connected with an anode and a prefabricatedwire mesh cathode that is extendable to at least twice its preformedinitial length. The cathode in a preferred embodiment includes a singlechain of conductive wire links formed as alternating loops and twists oftwo strands of monofilament titanium wire.

Still another example apparatus has been disclosed for the delivery ofelectric current for interbody spinal arthrodesis. Electrical current isdelivered to an implant surgically implanted within the intervertebralspace between two adjacent vertebrae of the spine to promote bone growthand the fusion process to areas adjacent to the implant. The implant isself-contained with a surgically implantable, renewable power supply andrelated control circuitry for delivering electrical current directly tothe implant and thus directly to the area in which the promotion of bonegrowth is desired. The desired areas of bone growth promotion areintended to be controlled by conducting negative charge only to thedesired location of promotion.

A further disclosed example provides direct current stimulation ofspinal interbody fixation device has also been disclosed. A spinalfusion stimulator has an interbody fustion cage or other interbodyfixation device adapted to be implanted in the intervertebral disc spaceof a patient's spine, the interbody fusion cage having a hollow bodywith internal and external conductive surfaces. The stimulator includesa constant current generator connected to the interbody fusion cage andset to provide a DC current effective to produce a surface currentdensity of at least 1 uA/cm² in the interbody fusion cage whenimplanted.

Additional long-term electrical delivery implant devices and relatedmethods have been disclosed for other intended uses related for exampleto neural stimulation, nerve regeneration, and muscle stimulation.

At least one published example provides for nerve regeneration by way ofelectrical stimulus as follows. In vivo mammalian nerve regeneration ofa damaged nerve is attempted by using an electric current through thedamaged nerve while the nerve ends are abutted against one another,sutured together or spaced apart from each other. The apparatus isintended to be implantable in a human body so that the electric currentcan be maintained for an extended period of time to produce regenerationof the damaged nerve.

Various disclosures have also intended to provide percutaneousintramuscular stimulation electrodes, such as for treating shoulderdysfunction in patients who have suffered disruption of the centralnervous system such as a stroke, traumatic brain injury, spinal cordinjury, or cerebral palsey. An external microprocessor basedmulti-channel stimulation pulse train generator is used for generatingselect electrical stimulation pulse train signals. In another example, aclosed-loop, implanted-sensor (e.g. force sensor), functional electricalstimulation system for partial restoration of motor functions isprovided.

Further more detailed examples of devices, systems, and methods similarto those described above, such as with respect to long-term energydelivery implants, spinal therapy implants, or related devices andmethods providing additionally helpful understanding, are variouslydisclosed in one or more of the following issued U.S. Patents: U.S. Pat.No. 4,569,351 to Tang; U.S. Pat. No. 4,750,499 to Hoffer; U.S. Pat. No.4,774,967 to Zanakis et al.; U.S. Pat. No. 5,031,618 to Mullett; U.S.Pat. No. 5,282,468 to Klepinski; U.S. Pat. No. 5,342,409 to Mullett;U.S. Pat. No. 5,417,719 to Hull et al.; U.S. Pat. No. 5,441,527 toErickson et al.; U.S. Pat. No. 5,501,703 to Holsheimer et al.; U.S. Pat.No. 5,565,005 to Erickson et al.; U.S. Pat. No. 5,643,330 to Holsheimeret al.; U.S. Pat. No. 5,766,231 to Erickson et al.; U.S. Pat. No.5,824,021 to Rise; U.S. Pat. No. 6,014,588 to Fitz; U.S. Pat. No.6,038,480 to Hrdlicka et al.; U.S. Pat. No. 6,112,122 to Schwardt etal.; U.S. Pat. No. 6,120,502 to Michelson; U.S. Pat. No. 6,169,924 toMeloy et al.; U.S. Pat. No. 6,171,239 to Humphrey; U.S. Pat. No.6,270,498 to Michelson; U.S. Pat. No. 6,292,699 to Simon et al.; U.S.Pat. No. 6,319,241 to King et al.; and U.S. Pat. No. 6,436,098 toMichelson. Additional devices, systems, and methods are disclosed in thefollowing U.S. Patent Application Publications: US 2001/0053885 toGielen et al., now U.S. Pat. No. 6,795,737; 2002/0111661; 2003/0014088to Fang et al. now U.S. Pat. No. 6,485,271. Additional examples are alsodisclosed in the following PCT Patent Application Publications: WO99/56818 to Racz; and WO 00/78389 to Fitz. Another device is shown inthe following U.S. Design Patent: Des. 361,555 to Erickson et al. Thedisclosures of these references listed variously throughout thisparagraph are herein incorporated in their entirety by referencethereto.

Notwithstanding substantial benefits gained by many of the long-termimplantable devices and chronic therapy methods previously described,each generally has respective limitations and shortcomings concomitantwith their specified indications for use and with respect to certaintherapies to which they are not generally applicable.

For example, the various disclosed not generally adapted to providethermal therapy the many electrical therapy devices described arespecially adapted to provide electrical nervous stimulus, and. Even tothe extent thermal therapy may or would be delivered, however, suchelectrical devices and methods have shortcomings in their ability todeliver adequate thermal therapy to tissue as required, in particular inand around the spine, and in particular in a manner that penetratesstructures sufficient to provide relatively deep heating from the energydelivery element, and/or that is controlled, directed, or focused forhighly localized thermal treatment. Moreover, the various previouslydisclosed references do not adequately accommodate the need to controland isolate temperatures if thermal therapy were to be delivered, whichis highly advantageous in particular during thermal treatment ofstructures in and around the spinal cord.

Still further, none of the previous disclosures noted above provideadequate devices and/or methods for controlling long-term thermaltherapy of various tissues associated with skeletal joints, again inparticular the spine, in order to achieve isolated, desired results suchas thermal remodeling of tissue support structures (in particularstressed structures such as collagenous tissues of intervertebraldiscs), controlled cellular necrosis (including either in combinationwith or exclusive of tissue remodeling), or cellular regeneration orstimulation, or enhanced drug delivery.

At least two ultrasound systems and methods have been disclosed that areintended to provide ultrasound energy delivery to tissue via long-termimplantable devices in order to treat chronic medical conditions such asof the types generally introduced above with primary respect toelectrical energy delivery.

For example, ultrasonic techniques have been disclosed for usingultrasonic imaging to assist in neurostimulator control wherein theprimary therapeutic energy delivery is electrical. A lead adapted to beimplanted adjacent to a spinal cord located within a spinal column of avertebrate in order to facilitate stimulation of the spinal cord oradjacent tissue. An ultrasonic transmitter/receiver produces anultrasonic sound wave that creates ultrasonic echo waves reflected froma predetermined portion of the spinal cord and generates a distancesignal related to the distance between the transducer/receiver and thepredetermined portion of the spinal cord. The distance signal is used toadjust the amplitude of an electrical stimulation signal that stimulatesthe spinal cord or adjacent tissue so that the value of the stimulationsignal tends to remain uniform in spite of changes in the relativedistance between the transducer/receiver and the predetermined portionof the spinal cord. Accordingly, such use of ultrasound is as adiagnostic tool, and generally not therapeutic US energy delivery.

In another example, an apparatus and method that stimulates withultrasound the growth of a tissue or produces an image at a site withina patient is disclosed. A housing may be subcutaneously implanted withinthe patient such that the ultrasound is directed toward the site. Agenerator disposed within the housing produces a signal, which atransducer converts into ultrasound. The transducer is partiallydisposed within the housing. The device may include an imaging circuitfor processing ultrasound echoes received by the transducer to generateimages of the tissue at the site. A remote control may be used tocontrol the device while it is implanted within the patient.

Further more detailed examples of ultrasound devices and methods relatedto neurostimulator control and/or stimulating tissue growth aredisclosed in the following issued U.S. Patents: U.S. Pat. No. 5,524,624to Tepper et al.; and U.S. Pat. No. 5,628,317 to Starkebaum et al. Thedisclosures of these references are herein incorporated in theirentirety by reference thereto.

Despite the benefits that such implantable ultrasound devices provide,they are still limited as to the ability to provide a wide variety ofimportant long-term ultrasound therapies via permanent or semi-permanentimplantable transducers. Moreover, other desirable features that are notprovided by various of the prior electrical stimulation systems andmethods are also not provided by these ultrasound devices and methods.

There is still a need for a long-term thermal or ultrasound therapyimplant system that is adapted to provide one or more of the followingbeneficial features affecting the desired therapy: active and localizedcooling of targeted and/or non-targeted tissues, use of ultrasonicallytransmissive coupling members to enhance energy delivery at the tissueinterface, directionality, focusing and/or collimation of the US energydelivery, substantial depth of heating, and temperature and dosingcontrols around values adapted to provide various intended tissueresponses (in particular within stressed tissues such as in spinaljoints).

Moreover, the devices and related noted above lack the ability toprovide additional benefits that may be harnessed from controlled,long-term ultrasound energy delivery into certain tissues in order toachieve a variety of desired tissue responses.

There is still a need for an improved, long-term implantable thermaltherapy system that can be activated when necessary over prolongedperiods of time in order to provide long term therapy to patients'joints, such as in particular spinal joints, in addition to othertissues in the body.

There is in particular still a need for a long-term, implantableultrasound therapy system adapted to provide long-term ultrasounddelivery to treat chronic ailments not adequately treated or cured byacute thermal therapy treatments.

There is also still a need for providing long-term thermal therapy totissue, and in particular stressed tissue such as found in spinaljoints, that allows for sufficient thermal doses to be delivered toachieve certain intended results according to lower elevatedtemperatures and over longer periods of time than otherwise currentlyavailable.

There is also still a need for a long-term implantable thermal therapysystem and method that is adapted to provide long term, directionalenergy delivery into tissue within the body, in particular tissueassociated with joints, and further more particularly spinal joints.

There is still a need for a system and method for locally deliveringtherapeutic amounts of ultrasound energy from long term implants withinthe body in order to treat disorders associated with the spine and otherjoints or tissues.

There is also still a need for a system and method adapted to locallydeliver ultrasound energy to a highly localized region of tissue, suchas only a portion of a disc associated with a spinal joint, when neededover long periods of time and without requiring multiple, repeatsurgeries.

BRIEF SUMMARY OF THE INVENTION

An object of the invention is to deliver long-term, therapeutic levelsof ultrasound energy to intervertebral discs in order to treat disordersassociated therewith.

Another object of the invention is to provide a kit of long-term,implantable energy delivery devices with varied shapes along the energydelivery portion thereof in order to specifically treat differentregions of intervertebral discs having varied geometries from within thenucleus.

Another object of the invention is to deliver therapeutic levels ofenergy over long-term duration and sufficient to cause necrosis ofparticular cellular structures associated with an intervertebral discwithout substantially remodeling or affecting the structure integrity ofthe annulus fibrosus of the disc.

Another object of the invention is to provide long-term, thermal therapyto a region of tissue associated with a joint in the body withoutsubstantially remodeling structural support tissues associated with thejoint.

Another object of the invention is to treat chronic inflammation andpain associated with disorders of the spine in general andintervertebral discs in particular.

Another object of the invention is to denervate or necrose nociceptivefibers or cells in certain regions of tissue associated with anintervertebral disc.

Another object of the invention is to reduce chronic inflammationassociated with damaged intervertebral discs.

Another object of the invention is to provide long-term implantabledevices for repairing damaged regions of intervertebral discs.

Another object of the invention is to achieve cellular necrosis ofcertain particular tissues associated with an intervertebral discdisorder without substantially altering the structure of the annulusfibrosus of the respective disc.

Another object of the invention is to remodel cartilaginous tissueassociated with spinal joints, and in particular intervertebral discs.

Another object of the invention is to provide sufficient thermal therapyto a region of stressed tissue to cause a remodeling of the tissue overprolonged treatment periods.

Another object of the invention is to provide sufficient thermal therapyto a region of an intact mammalian intervertebral disc to cause aremodeling of at least one support structure.

Another object of the invention is to provide a thermal therapy devicethat can substantially heat deep regions of tissue from the site oftherapy, such as with respect to spinal joints at least about 4 mm, 7mm, or even 10 mm from the site of therapy.

Another object of the invention is to provide therapeutic levels ofthermal therapy to tissue within relatively short durations of energydelivery, though over relative long-term duration of overall therapy.

Another object of the invention is to direct therapeutic energy intotargeted tissues from remote locations within the body, such as in oraround joints, without substantially harming closely adjacent tissues,such as nerves, vessels, or other tissues not intended to be treated.

Another object of the invention is to focus energy into targeted regionsof tissue within the body.

Another object of the invention is to enhance cellular functions incertain tissue structures so as to provide a therapeutic effect.

Another object of the invention is to enhance drug delivery intoremotely located body tissues, such as within or around joints such asspinal joints.

Another object of the invention is to treat chronic back pain.

Another object of the invention is to treat chronic arthritis.

Another object of the invention is to locally enhance the delivery,permeability, or cellular uptake related to certain therapeuticcompounds delivered within the spine and other joints.

Accordingly, one aspect of the invention is an ultrasound energydelivery system for providing long term treatment to a region of tissueassociated with a skeletal joint. The system includes a long-termimplantable ultrasound treatment assembly with an ultrasound transducer,and a skeletal joint delivery assembly that is adapted to deliver theultrasound treatment assembly into the body with the ultrasoundtransducer positioned at a location within the body associated with theskeletal joint. The ultrasound treatment assembly is adapted to providelong-term delivery of a therapeutic level of ultrasound energy from thelocation and into the region of tissue.

According to one mode of this aspect, a controller is provided that isadapted to couple with and control the ultrasound transducer, and thatalso a long-term implant that is adapted to be implanted within the bodyof the patient. In one embodiment, the controller includes a powersource, which may in a further regard be rechargeable such as arechargeable battery. In a further variation, the power source isadapted to be recharged by exposure to a magnetic field across a skinbarrier of the patient.

According to further modes, the controller includes one or more of amicroprocessor, a monitoring assembly, and/or a data storage system.

In another mode, the controller is adapted to communicate across thepatient's skin barrier via wireless communications system so as toprovide telemetry with respect to the ultrasound therapy.

In another mode, the system further comprises an external assembly thatis adapted to communicate with the controller via wireless signals so asto receive telemetry with respect to the ultrasound therapy.

According to another aspect of the invention, a long-term implantableultrasound controller is provided that is adapted to control ultrasoundenergy delivery from a long-term implantable ultrasound treatmentassembly. In one mode, the controller is adapted to operate theultrasound treatment assembly according to a set of operating parametersadapted to stimulate bone growth. In a further embodiment of this mode,the set of operating parameters comprises: a transmission power levelbetween about 0.1 to about 1 W/cm2, and about 1.5 MHz, and at about 1kHz repetition, and with burst intervals between about 100 to about 200micro-seconds. In another embodiment, the set of parameters furtherincludes: total aggregate time of ultrasound delivery is between about10 to 30 minutes per day for at least one day of long-term ultrasoundtreatment.

According to another mode, the controller is adapted to operate theultrasound treatment assembly according to a set of operating parametersadapted to enhance drug delivery therapy to the tissue at the location.In one embodiment of this mode, the set of operating parametersincludes: transmission power between about 0.5 to about 2 W/cm2,operating frequency between about 5 to about 12 MHz, and continuous wavedelivery. In a further embodiment, the set of parameters furthercomprises: aggregate time of ultrasound delivery between about 5 toabout 60 minutes per day over at least one day of long-term ultrasoundtreatment.

In another mode, the controller is adapted to operate the ultrasoundtransducer according to the following set of ultrasound operatingparameters: transmission power between about 1 to about 30 W/cm2,transmission bursts lasting between 50 to 200 microseconds, repetitionbetween bursts between about 1 Hz to about 5 kHz, and at ultrasoundoperating frequencies between about 0.5 to about 15 MHz.

In another mode, the controller is adapted to operate the ultrasoundtransducer at operating frequencies between about 12 to about 15 MHz.

In another mode, the controller is adapted to operate the ultrasoundtransducer so as to provide thermal therapy in addition to acousticnervous stimulation.

In another mode, the controller is adapted to operate the ultrasoundtreatment assembly according to a set of ultrasound operating parametersadapted to stimulate nervous impulses at the location.

According to one embodiment of this mode, the set of operatingparameters includes: pulsed ultrasound delivery over periods of lessthan or equal to about 70 microseconds, and operating frequency of about5 MHz.

In another mode, the controller is adapted to operate the ultrasoundtreatment assembly according to a set of ultrasound operating parametersadapted to accomplish at least one of: regenerate peripheral nerves,repair pseudarthrosis and bone fractures, stimulate bone growth, andstimulate osteogenesis with respect to repairing fractures.

In one embodiment of this mode, the set of ultrasound operatingparameters includes: transmission power of about 0.5 W/cm2, operatingfrequency of about 1.5 MHz, treatment interval durations of betweenabout 5 to about 25 minutes per day for at least one day over along-term treatment regimen. In a further variation, the set ofoperating parameters further includes a total period of therapy of aboutfour weeks.

In another mode, the set of ultrasound operating parameters includes:ultrasound transmission at about 0.5 W/cm² aggregate daily treatment ofabout 15 minutes per day for at least one day over a long-term treatmentregime.

Another aspect of the invention is a skeletal joint therapy device andincludes a long-term implantable thermal treatment assembly with anenergy emitter. The thermal treatment assembly is adapted to beimplanted at a location within a body of a patient. The energy emitteris adapted to follow a long-term protocol for energy delivery into aregion of tissue associated with a skeletal joint, such that the thermaltreatment assembly is adapted to heat tissue up to a distance of atleast 4 mm from the energy emitter to a temperature of at least 75degrees C., and is adapted to heat tissue up to a distance of at leastabout 7 mm from the energy emitter to a temperature of at least about 55degrees C., and is adapted to heat tissue up to a distance of at leastabout 10 mm from the energy emitter to a temperature of at least about45 degrees C.

In a highly beneficial mode of this aspect, the thermal treatmentassembly includes an ultrasound transducer.

In another mode, the device further comprises a long-term implantablecontroller that is adapted to be coupled to and control operation of thethermal treatment assembly according to the long-term protocol andaccording to a set of operating parameters.

Another aspect of the invention is a long-term implantable ultrasoundthermal treatment system, and includes a long-term implantableultrasound treatment assembly with an ultrasound transducer, and along-term implantable coupling probe having a elongate body with aproximal end portion and a distal end portion. The distal end portionhas a proximal section with a longitudinal axis, a distal section with adistal tip, and a bend between the proximal and distal sections. Theultrasound treatment assembly is located along the distal section of thedistal end portion and extending at an angle from the proximal section.The distal end portion is adapted to be implanted within the body of amammal by manipulating the proximal end portion such that the ultrasoundtreatment assembly is positioned at a location associated with a regionof tissue to be treated. The proximal end portion is also adapted to beimplanted within the body with the distal end portion implanted with theultrasound treatment assembly at the location. The ultrasound treatmentassembly is adapted to follow a long-term therapeutic protocol ofultrasound energy delivery into the region of tissue from the locationwithin the body.

Another aspect of the invention is a long-term implantable ultrasoundthermal therapy system with a long-term implantable ultrasound heatingassembly with an ultrasound transducer and that is adapted to beimplanted within a body of a mammal with the ultrasound transducerpositioned at a location such that the ultrasound transducer is adaptedto deliver a ultrasound energy into a targeted region of tissue in thebody from the location. Also includes is a long-term ultrasound therapycontrol system that is adapted to be coupled to the ultrasound heatingassembly. The long-term implantable ultrasound therapy control system isadapted to be coupled to and control operation of the ultrasound heatingassembly while it is implanted at the location according to a long-termultrasound thermal therapy protocol.

Another aspect of the invention is a long-term directional ultrasoundspinal thermal therapy system that includes a long-term implantableultrasound delivery assembly with a directional ultrasound transducerthat is adapted to be positioned at a location associated with a spinaljoint and to deliver a directed, therapeutic amount of ultrasound energyfrom the location and to a region of tissue associated with the spinaljoint.

Another aspect of the invention is a long-term implantable skeletaljoint ultrasound delivery system with a long-term implantable ultrasoundtreatment assembly with an ultrasound transducer and a coupling member.The ultrasound delivery assembly is adapted to be implanted within abody of a mammal with the ultrasound transducer positioned at a locationwithin the body associated with a skeletal joint. The ultrasoundtransducer is adapted to deliver a therapeutic amount of ultrasoundenergy to a region of tissue associated with the skeletal joint via thecoupling member and according to a long-term ultrasound treatmentprotocol.

Another aspect of the invention is a long-term implantable ultrasoundthermal therapy system that includes a long-term implantable ultrasoundheating assembly that is adapted to be implanted at a location within abody of a mammal so as to deliver ultrasound energy into a region oftissue in the body from the location. This system also includes acontrol system that is adapted to be coupled to the ultrasound heatingassembly and to control operation of the ultrasound heating assemblyaccording to a long-term ultrasound thermal therapy protocol and suchthat a region of tissue being heated by the ultrasound heating assemblyexceeds a temperature of at least about 70 degrees C.

Another aspect of the invention is an ultrasound thermal therapy systemwith a long-term implantable ultrasound heating assembly that is adaptedto be implanted within a body of a patient and to couple with anultrasound controller from the location, and also with a curvilinearultrasound transducer having a concave surface with a radius ofcurvature around a reference axis such that ultrasound energytransmitted therefrom converges into a region of tissue at a targetlocation.

Another aspect of the invention is a method for providing long-term,invasive treatment for a medical condition associated with a skeletaljoint within a body of a patient. This method aspect includes deliveringa therapeutic level of ultrasound energy to a region of tissueassociated with the joint from a location within the body of the patientand according to a long-term ultrasound therapy protocol.

Another aspect of the invention is a method for providing long-term,invasive treatment for a medical condition associated with a skeletaljoint within a body of a patient. This method aspect includes deliveringsufficient energy to a region of tissue associated with the skeletaljoint that is sufficient to necrose nociceptive nerve fibers orinflammatory cells in such tissue region without substantially affectingcollagenous structures associated with the skeletal joint and accordingto us of a long-term energy delivery implant and according to along-term energy delivery therapeutic protocol.

Another aspect of the invention is a method for providing long-term,invasive treatment to a region of tissue associated with anintervertebral disc in a body of a patient. this method aspect includesimplanting a long-term ultrasound transducer implant at a locationwithin the body such that a therapeutic level of ultrasound may becoupled from the transducer to the tissue and according to a long-termultrasound therapy protocol.

Other method aspects of the present invention with respect to providinglong term tissue therapy via long-term implants include variouslong-term implantable adaptations of other aspects elsewhere hereindescribed.

Another aspect of the invention is an implantable spinal thermal therapysystem with a spinal delivery system and a spinal thermal therapydevice. The spinal delivery system is adapted to deliver a thermaltherapy assembly of the spinal thermal therapy device to a locationwithin the body such that the energy may be coupled to a region oftissue associated with a vertebral joint.

Another aspect of the invention is an ultrasound energy delivery systemfor treating a region of tissue associated with a skeletal joint, andincludes an ultrasound treatment assembly with an ultrasound transducer;and a skeletal joint delivery assembly. The skeletal joint deliveryassembly is adapted to deliver the ultrasound treatment assembly intothe body with the ultrasound transducer positioned at a location withinthe body associated with the skeletal joint. The ultrasound treatmentassembly is adapted to deliver a therapeutic level of ultrasound energyfrom the location and into the region of tissue.

Another aspect of the invention is a skeletal joint thermal therapydevice with a thermal treatment assembly on the distal end of a deliverymember. The thermal treatment assembly includes an energy emitter. Thedistal end portion is adapted at least in part to deliver the thermaltreatment assembly into a body of an animal with the energy emitterpositioned at a location such that the energy emitter is adapted todeliver energy into a region of tissue associated with a skeletal joint.The thermal treatment assembly is adapted to heat tissue up to adistance of at least 4 mm from the energy emitter to a temperature of atleast 75 degrees C., and is adapted to heat tissue up to a distance ofat least about 7 mm from the energy emitter to a temperature of at leastabout 55 degrees C., and is adapted to heat tissue up to a distance ofat least about 10 mm from the energy emitter to a temperature of atleast about 45 degrees C.

Another aspect of the invention is an ultrasound thermal treatmentsystem with an ultrasound treatment assembly with an ultrasoundtransducer on a distal end portion of a rigid delivery probe. Theprobe's distal end portion has a proximal section with a longitudinalaxis, a distal section with a distal tip, and a bend between theproximal and distal section. The ultrasound treatment assembly islocated along the distal section of the distal end portion and extendingat an angle from the proximal section. The distal end portion is adaptedto be delivered into the body of an animal by manipulating the proximalend portion externally of the body and such that the ultrasoundtreatment assembly is positioned at a location associated with a regionof tissue to be treated. Moreover, the ultrasound treatment assembly isadapted to deliver a therapeutic level of ultrasound energy into theregion of tissue from the location within the body.

Another aspect of the invention is an ultrasound thermal therapy systemwith an ultrasound heating assembly with an ultrasound transducer and atherapy control system coupled to the ultrasound heating assembly. Theultrasound heating assembly is adapted to be delivered into a body of ananimal with the ultrasound transducer positioned at a location such thatthe ultrasound transducer is adapted to deliver a therapeutic amount ofultrasound energy into a targeted region of tissue in the body from thelocation. The therapy control system is adapted to control operation ofthe ultrasound heating assembly such that a substantial portion of theregion of tissue being heated by the ultrasound heating assembly doesnot exceed a maximum temperature of at least about 70 degrees C.

Another aspect of the invention is a directional ultrasound spinalthermal therapy system with an ultrasound delivery assembly. Theultrasound delivery assembly has a directional ultrasound transducerthat is adapted to be positioned at a location associated with a spinaljoint and to deliver a directed, therapeutic amount of ultrasound energyfrom the location and to a region of tissue associated with the spinaljoint.

Another aspect of the invention is a skeletal joint ultrasound deliverysystem with an ultrasound treatment assembly with an ultrasoundtransducer and a coupling member. The ultrasound delivery assembly isadapted to be delivered into a body of a mammal with the ultrasoundtransducer positioned at a location within the body associated with askeletal joint. The ultrasound transducer is adapted to deliver atherapeutic amount of ultrasound energy to a region of tissue associatedwith the

Another aspect of the invention is an ultrasound thermal therapy systemwith an ultrasound heating assembly and a control system. The ultrasoundheating assembly is adapted to be positioned at a location within a bodyof a mammal so as to deliver ultrasound energy into a region of tissuein the body from the location. The control system is adapted to coupleto the ultrasound heating assembly and to control operation of theultrasound heating assembly such that a region of tissue being heated bythe ultrasound heating assembly exceeds a temperature of at least about70 degrees C.

Another aspect of the invention is an ultrasound thermal therapy systemwith a an ultrasound heating assembly located along the distal endportion of a delivery member. The ultrasound heating assembly has acurvilinear ultrasound transducer having a concave surface with a radiusof curvature around a reference axis that is transverse to thelongitudinal axis of the distal end portion.

Another aspect of the invention is a method for treating a medicalcondition associated with a skeletal joint within a body by deliveringsufficient energy to a region of tissue associated with the skeletaljoint that is sufficient to necrose nociceptive nerve fibers orinflammatory cells in such tissue region without substantially affectingcollagenous structures associated with the skeletal joint.

Another aspect of the invention is a method for treating a region oftissue associated with an intervertebral disc in a body of an animal bydelivering an ultrasound transducer to a location within the body suchthat a therapeutic level of ultrasound may be coupled from thetransducer to the tissue.

Another aspect of the invention is a method for treating an animal bydelivering energy to a region of tissue associated with the spine,wherein such energy delivery is between about 10 and about 300equivalent minutes at 43 degrees C.

Another aspect is a method for invasively treating a medical conditionassociated with an intervertebral disc within a body of animal bydelivering a therapeutic level of ultrasound energy to a region oftissue associated with an intervertebral disc from a location within thebody of the patient.

Another aspect of the invention is a method for treating medicalcondition associated with a joint between two bony structures in a bodyof an animal by delivering an ultrasound transducer to a location withinthe patient's body associated with the joint; and emitting ultrasoundenergy from the transducer at the location so as to provide atherapeutic effect to at least a portion of the joint.

Another aspect of the invention is a method for treating an animal byintroducing an ultrasound transducer into a body of the animal;positioning the ultrasound transducer at a location within the animalthat is adjacent to at least one of an annulus fibrosus of anintervertebral disc, a nucleus pulposus of the intervertebral disc, or avertebral body associated with a spinal joint in the body; and emittingultrasound energy from the ultrasound transducer at the location.

Another aspect of the invention is a method for providing ultrasoundenergy delivery within a body of an animal by introducing an ultrasoundtransducer into a body of a patient; positioning the ultrasoundtransducer at a location within the patient that is within at least oneof an annulus fibrosus of an intervertebral disc, a nucleus pulposus ofthe intervertebral disc, or a vertebral body associated with a spinaljoint in the body; and emitting ultrasound energy from the ultrasoundtransducer at the location.

Another aspect of the invention is a method for treating a patient byultrasonically heating a region of tissue associated a spinal joint to atemperature between about 45 to about 90 degrees Fahrenheit forsufficient time to cause a therapeutic result in the tissue.

Further objects and advantages of the invention will be brought out inthe following portions of the specification, wherein the detaileddescription is for the purpose of fully disclosing preferred embodimentsof the invention without placing limitations thereon.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will be more fully understood by reference to thefollowing drawings which are for illustrative purposes only:

FIG. 1A shows a side perspective view of an illustration of a typicalhuman spine for treatment according to the systems and methods of theinvention.

FIG. 1B shows an exploded, cross-sectioned side view of the regiondepicted as 1B in FIG. 1A, and shows an intervertebral disc between twoadjacent vertebral bodies.

FIG. 2 shows an angular perspective view of a transverselycross-sectioned intervertebral disc in relation to adjacent spinalstructures.

FIG. 3A shows an angular perspective view of an ultrasonicintervertebral disc therapy system according to the invention, andincludes a partially segmented view of an ultrasound treatment device, aschematic view of an ultrasound drive system, and an angular perspectiveview of an introduction device, respectively, of the system.

FIG. 3B shows a longitudinal side view taken along lines 3B-3B in FIG.3A.

FIG. 3C shows a transverse cross-sectioned view taken along lines 3C-3Cin FIG. 3A.

FIG. 4 shows a transverse cross-sectioned view of the distal end portionof another ultrasound treatment device of the invention with a differentsupport structure under the ultrasound transducer of the device than thesupport structure shown in FIG. 3C.

FIG. 5A shows a slightly angled side view of the distal end portion ofanother ultrasound treatment device according to the invention, and alsoshows a schematic view of a guide wire included in the system.

FIG. 5B shows a cross-sectioned side view of the device taken alonglines 5B-5B in FIG. 5A.

FIG. 6A shows a slightly angled side view of an ultrasound transducercomponent assembly for use in the distal end portion of anotherultrasound treatment device according to the invention.

FIG. 6B shows a cross-sectioned transverse view taken along lines 6B-6Bin FIG. 6A.

FIG. 6C shows a schematic cross-sectioned side view of an alternativeultrasound transducer component assembly within an ultrasound treatmentdevice according to the invention versus that shown in FIG. 6B.

FIG. 6D shows an angular perspective view of a semi-sphericaldisc-shaped transducer for use according to a further embodiment of theinvention.

FIGS. 7A-F show a top perspective view of a laterally cross-sectionedintervertebral disc during respectively sequential modes of operatingthe ultrasound treatment system for intervertebral disc therapyaccording to the invention.

FIGS. 8-9 show alternative modes of operating an ultrasound treatmentdevice according to the invention for treating different respectiveregions of an annulus fibrosus of a disc from within the nucleus andaccording to a posterior-lateral approach into the disc.

FIG. 10 shows an alternative mode of operating an ultrasound treatmentdevice according to the invention using an anterior approach to treat aposterior wall region of the annulus fibrosus of a disc from within thenucleus of the disc.

FIGS. 11-13 show alternative modes of operating an ultrasound treatmentdevice for treating different respective regions of an annulus fibrosusof a disc from externally of the annulus fibrosus and without enteringthe nucleus, wherein FIGS. 11 and 13 show a posterior-lateral approachto right lateral and posterior wall regions of the annulus,respectively, and FIG. 12 shows an anterior approach to a left lateralwall region of the annulus.

FIGS. 14A-B show plan perspective views of the distal end portion ofanother ultrasound treatment device of the invention during variousmodes of operation, wherein FIG. 14A shows a straight configuration forthe device, and FIG. 14B shows two modes of angular deflection for thedistal end portion of the device.

FIG. 14C shows a top perspective view of another ultrasound treatmentdevice of the invention with a distal ultrasound treatment section thatis adapted to be rotated about a hinge point for minimally invasivetreatment of intervertebral discs and other spine or joint disorders.

FIG. 15A shows a plan perspective view of the distal end portion ofanother ultrasound treatment device of the invention having apredetermined shape and operative region for ultrasound delivery thatcorresponds to particular desired approaches and ultrasound therapy tocertain specified regions of tissue associated with an intervertebraldisc.

FIG. 15B shows a perspective view of another ultrasound treatment devicehaving a similar shape to that shown in FIG. 15A, but having a differentoperative region for ultrasound delivery corresponding to deliveringinvasive therapy to a different desired region of a respectiveintervertebral disc.

FIG. 16 shows a perspective view of another ultrasound treatment devicehaving a different unique shape and operative region for ultrasounddelivery corresponding to delivering invasive therapy to a differentdesired region of a respective intervertebral disc.

FIG. 17A shows a top view of an ultrasound treatment device assemblywith transducers inside of an outer cooling jacket that is interfacedwith a fluid circulation pump to actively cool the transducers.

FIG. 17B shows a top view of another partially cross-sectionedultrasound treatment device assembly similar to that shown in FIG. 17A,except showing the cooling fluid to circulate from within the ultrasoundtransducer device and into the surrounding sheath.

FIG. 18A shows an x-ray picture of an explanted disc being treatedaccording to one aspect of the invention, and shows various data pointsalong temperature monitoring probes inserted along certain desiredlocations for monitoring across the disc.

FIG. 18B shows a graph of temperature vs. time for an ultrasound heatingstudy in an explanted cadaver spine disc, and shows curves for tissuedepths of 1 mm, 4 mm, 7 mm, and 10 mm away from the directional heatingtransducer.

FIG. 19 shows a typical modulus versus applied stress plot according toa study performed in Example 2, and shows results before (solid line)and after (dashed line) heat treatment at 85° C., and indicates thefollowing biomechanical parameters: change in modulus at the inflectionpoint (MI), change in modulus at 150 kPa (M150), and change in residualstress at the inflection point (RSI).

FIG. 20 shows a typical stress-strain plot before (solid line) and after(dashed line) treatment at 85° C., and shows for each cycle an upperline indicating the loading phase, and a lower curve indicating theunloading phase.

FIG. 21 shows graphs (a)-(e) that variously represent respective changesin certain tissue parameters that were observed after varied heattreatments.

FIG. 22 shows various light microscopy photographs of various tissuesamples, and includes bright light (left panel) and polarized light(right panel) microscopy of specimens treated, and shows pictures (a, b)for samples intact at 37° C.; pictures (c, d) for intact samples at 85°C.; and pictures (d, e) representing excised at 85° C.

FIG. 23 shows a schematic side view of a distal end portion of anexternal directional ultrasound thermal treatment (“ExDUSTT™”) device ofthe invention incorporating a directional, focused ultrasound emitterassembly that is adapted for external use adjacent to an intervertebraldisc.

FIG. 24 shows an illustrated side view of a partially cross-sectionedultrasound spinal treatment assembly similar to that shown in theExDUSTT device shown in FIG. 23, and shows the assembly during one modeof use in treating a region of an intervertebral disc associated with aspinal joint.

FIG. 25 shows a plan view of a distal end portion of a further ExDUSTTembodiment that incorporates a substantially rigid, pre-shaped probedevice platform.

FIG. 26 shows a plan view of a distal end portion of another ExDUSTTdevice embodiment that incorporates a substantially flexible, catheterdevice platform according to another embodiment of the invention.

FIG. 27A shows a longitudinally cross-sectioned view of a distal endportion of an ExDUSTT device on a rigid probe platform similar to thatshown in FIG. 25, and shows a substantially compliant elastomericballoon over a curvilinear ultrasound transducer.

FIG. 27B shows a transverse cross-sectioned view through an ultrasoundtransducer mounting region of the ExDUSTT device shown in FIG. 27A.

FIG. 28A shows a longitudinally cross-sectioned view of a distal endportion of another ExDUSTT device on a rigid probe platform that is alsosimilar to that shown in FIG. 25, except with a substantiallynon-compliant pre-formed balloon over the curvilinear ultrasoundtransducer.

FIG. 28B shows a transverse cross-sectioned view through an ultrasoundtransducer mounting region of the ExDUSTT device shown in FIG. 28A.

FIG. 29A shows a transverse cross-sectioned view of a distal end portionof another ExDUSTT device on a polymeric catheter delivery chassissimilar to that shown in FIG. 26, and shows a substantially compliantelastomeric balloon over a transversely aligned, curvilinear ultrasoundtransducer.

FIG. 29B shows a transverse cross-sectioned view through an ultrasoundtransducer mounting region of the ExDUSTT device shown in FIG. 29A.

FIG. 30A shows a transverse cross-sectioned view of a distal end portionof another ExDUSTT device on a catheter delivery platform similar tothat shown in FIG. 29A, except with an axially aligned, curvilinearultrasound transducer within a substantially compliant elastomericballoon.

FIG. 30B shows a transverse cross-sectioned view through an ultrasoundtransducer mounting region of the ExDUSTT device shown in FIG. 30A.

FIGS. 31A-B show two respective graphs for acoustic efficiency andacoustic output power, respectively, for one exemplary workingembodiment of a rigid probe ExDUSTT device similar to that shown in FIG.25.

FIGS. 32A-B show two respective graphs for acoustic efficiency andacoustic output power, respectively, for one exemplary workingembodiment of a catheter-based ExDUSTT device similar to that shown inFIG. 26.

FIG. 33 shows a schematic drawing of an ultrasound heating assemblyportion of a catheter-based ExDUSTT device similar to that shown in FIG.26 superimposed over an X-ray picture of the intervertebral disc toillustrate one experimental set-up to evaluate the device, and alsoshows superimposed reference numbers designating certain monitoredtemperatures at various locations within the disc during one mode oftreatment.

FIG. 34A-B show two respective graphs of temperature monitored over timeat various thermocouples locations 105(C)-109(C) during two respectivein-vivo thermal therapy treatments in an intervertebral pig disc using acatheter-based ExDUSTT device similar to that shown in FIG. 26 andaccording to an experimental set-up similar to that shown in FIG. 33.

FIG. 35 shows two, respective ExDUSTT devices of pre-shaped, rigid probeconstruction similar to that shown in FIG. 25, except the devices shownare constructed according to different size embodiments incorporatingultrasound transducers having varied respective widths of 2.5 mm and 3.5mm, respectively.

FIGS. 36A-B show top and angular perspective views, respectively, ofcertain power output profile across the face of the 2.5 mm widetransducer shown in FIG. 35A.

FIGS. 37A-B show top and angular perspective views, respectively, ofcertain power output profiles across the face of the 3.5 mm widetransducer shown in FIG. 31B.

FIG. 38 shows an X-ray picture of a top view of an ex-vivo experimentalarrangement similar to that shown schematically in FIG. 33, exceptshowing a directional ultrasound heating assembly of a workingembodiment for a probe-based ExDUSTT device such as shown in FIG. 25positioned for desired heating of an intervertebral disc according toone modes of use, and shows various thermocouple probes within the discto monitor experimental temperatures.

FIG. 39 shows an exploded view of the same Ex-DUSTT intervertebral disctreatment arrangement shown for the 3.5 mm probe-like ExDUSTT device inFIG. 38, and shows monitored temperature values at various respectivelocations along the axial and radial temperature probes during onerelatively high temperature mode of use with active cooling at 0 degreesC.

FIG. 40 shows a graph of temperature vs. time for the varioustemperature probes according to the thermal therapy arrangement shown inFIG. 39.

FIG. 41 shows a graph of temperature monitored along the 5 mm and 10 mmdeep axial temperature sensor probes and the radial temperature sensorprobes shown within the intervertebral disc and during treatment withthe probe-based ExDUSTT with the 3.5 mm wide transducer shown in FIG.38, and according to an ex-vivo study performed with active transducercooling at 0 degrees C.

FIG. 42 shows the same exploded view of the experimental arrangementshown in FIG. 39, except shows thermocouple values corresponding to arelatively low temperature mode of operation with room temperaturecooling.

FIG. 43 shows a similar graph of temperature vs. time as that shown inFIG. 40, except with respect to data measured according to thearrangement illustrated for FIG. 42.

FIG. 44 shows another graph of certain temperature vs. transducerposition results similar to the graph shown in FIG. 41, except showingresults according to the mode of operation also variously illustrated inFIGS. 42-43.

FIG. 45 shows a similar exploded X-ray picture to that shown in FIGS. 39and 42, except showing thermocouple values according to a relatively lowtemperature mode of operation using a 3.5 mm wide transducer and coolingat 0 degrees C.

FIG. 46 shows another temperature vs. time graph, except with respect tothe arrangement also illustrated in FIG. 45.

FIG. 47 shows a graph of temperature vs. thermocouple position resultsaccording to the thermal therapy arrangement illustrated in FIGS. 45 and46.

FIG. 48 shows another exploded X-ray picture of the same ExDUSTTarrangement, except according to use of a 2.5 mm wide transducer withrelatively low temperature heating mode and cooling at 0 degrees C.

FIG. 49 shows another temperature vs. time graph for the ExDUSTT heatingarrangement illustrated in FIG. 48.

FIG. 50 shows another temperature vs. thermocouple position graph for a2.5 mm curvilinear ExDUSTT ex-vivo disc treatment using 0 degree C.cooling and relatively low temperature mode of operation.

FIG. 51 shows another exploded X-ray picture, except with thermocouplevalues corresponding to use of a 2.5 mm transducer ExDUSTT device at arelatively low temperature mode of use with room temperature cooling.

FIG. 52 shows a temperature vs. time graph according to the ExDUSTT modeof therapy also illustrated in FIG. 51.

FIG. 53 shows a temperature vs. thermocouple position graph for themodes of ExDUSTT therapy illustrated in FIGS. 51 and 52.

FIG. 54 shows a perspective view of an internal directional ultrasoundthermal therapy system (“InDUSTT™”) that includes a spinal disc deliveryprobe and an InDUSTT device that fits within the spinal disc deliveryprobe.

FIG. 55A shows a plan view of a schematic representation of an internalultrasound thermal spine therapy device according to another embodimentof the invention.

FIG. 55B shows an exploded view taken at region B shown in FIG. 55A, andshows enhanced detail of various aspects of the ultrasound heatingassembly along the distal end portion of the InDUSTT system according toa further feature of that embodiment.

FIG. 55C shows a transverse cross-sectioned view taken along line C-C inFIG. 55A.

FIGS. 56A-B show respective X-ray pictures of the distal end portion ofan InDUSTT system similar to that shown in FIGS. 54-55B positionedwithin an intervertebral disc during in-vivo thermal spinal treatmentsaccording to certain modes of the invention.

FIG. 57 shows a table providing thermal dosimetry data collected duringcertain modes of in-vivo operation for various working embodiments of anInDUSTT system similar to that shown in FIGS. 54-55B and providingtherapeutic ultrasonic heating at various temperature modes of poweredoperation corresponding to C2/3, C3/4, C4/5, and C5/6 intervertebralsheep discs, respectively.

FIG. 58 shows various X-ray pictures of the placement of the InDUSTTtransducer within the C2/3, C3/4, C4/5, and C5/6 intervertebral discscorresponding to the results provided in the table in FIG. 57.

FIG. 59A shows a graph of temperature vs. time during InDUSTT heating ofa C3/4 intervertebral disc according to a relatively high temperaturemode of use, and shows curves for various respective thermocouple probepositions.

FIG. 59B shows a graph of temperature vs. time using the same InDUSTTdevice as that used for creating the data shown in FIG. 59A, exceptshows results according to a relatively low temperature mode of use in aC4/5 intervertebral disc location.

FIG. 59C shows a graph of temperature monitored at various temperaturesensor positions during 10 minute InDUSTT heating, and shows curves forresults in two separate intervertebral discs each heated with adifferent one of two separate InDUSTT systems of the invention.

FIG. 60 shows another table providing thermal dosimetry data collectedduring modes of in-vivo operation for various working embodiments of adirectly coupled InDUSTT system providing therapeutic ultrasonic heatingfrom within C2/3, C3/4, and C4/5 intervertebral discs of a sheep. Risetime is the period of time to reach target treatment temperature.T_(ave) is the average temperature during the 10 minute steady-statetreatment period. StDev_(Tave) is the standard deviation of temperatureduring 10 minute steady-state treatment period. Dose is the accumulateddose expressed in equivalent minutes at 43° C. (EM_(43C)).

FIG. 61 shows various respective X-ray pictures of certain transducerplacements for the directly coupled InDUSTT during in-vivo spinal discthermal therapy at the C2/3, C3/4, and C4/5 intervertebral sheep discscorresponding to the similarly designated rows of data illustrated inthe table of FIG. 60.

FIG. 62A shows a graph of temperature vs. time corresponding to the C2/3disc treatment shown in FIG. 61 and according to a relatively hightemperature mode of use.

FIG. 62B shows a graph of temperature vs. time corresponding to the C3/4disc treatment shown in FIG. 61, and according to a relatively lowtemperature mode of use.

FIG. 62C shows a graph of temperature monitored at various temperaturesensor positions during 10 minute directly coupled InDUSTT heating, andshows curves for thermal treatment results at both dead sectors andactive sectors of the transducer in the C2/3 disc at relatively hightemperature power level, and at similar locations in the C3/4 disc atthe corresponding, relatively low temperature power level.

FIG. 62D shows a graph of accumulated thermal dose versus temperaturesensor position for the 10 minute treatments at the C2/3 and C3/4 discsat the relatively high and low temperature power levels, respectively.

FIG. 63 shows another table providing thermal dosimetry data collectedduring modes of in-vivo operation for various working embodiments of acatheter cooled InDUSTT system providing ultrasonic heating from withinC2-3, C3-4, C4-5, and C5-6 intervertebral discs of a sheep.

FIG. 64 shows various respective X-ray pictures of certain transducerplacements for the catheter cooled InDUSTT during in-vivo thermal spinaldisc therapy at the C2-3, C3-4, C4-5 and C5-6 intervertebral discscorresponding to the similarly designated rows of data illustrated inthe table of FIG. 63.

FIG. 65A shows a graph of the relatively high temperature, cathetercooled InDUSTT therapy of the C2/3 disc as monitored over multipletemperature sensors along first and second temperature probes positionedwithin the disc.

FIG. 65B shows a temperature vs. time graph of the relatively lowtemperature mode of operation for the catheter cooled InDUSTT therapy inthe C3/4 disc and as monitored over multiple temperature sensors alongfirst and second temperature monitoring probes positioned within thedisc.

FIG. 65C shows a temperature vs. time graph of the relatively hightemperature, catheter cooled InDUSTT therapy of the C5/6 disc asmonitored over the multiple temperature sensors along first and secondtemperature monitoring probes positioned within the disc.

FIG. 65D shows a graph of temperature monitored at various axialpositions relative to the transducer during 10 minute catheter cooledInDUSTT heating, and shows curves for thermal treatment results atvarious locations in the C2/3 disc at relatively high temperature powerlevel, in the C3/4 disc at relatively low temperature power level, andC5/6 disc at relatively high temperature power levels.

FIGS. 66-68 show respective schematic views of different embodiments fora long-term implantable ultrasound spinal therapy device systemaccording to the present invention.

DETAILED DESCRIPTION OF THE INVENTION

Referring more specifically to the drawings, for illustrative purposesthe present invention is intended to provide thermal treatment to spinaljoints, and in particular intervertebral discs as illustrated in FIGS.1A-2, as embodied in the apparatus shown and characterized by way of thevarious modes of operation with respect to certain intended anatomicalenvironments of use variously throughout FIGS. 3-65D. It will beappreciated that the apparatus may vary as to configuration and as todetails of the parts, and that the method may vary as to the specificsteps and sequence, without departing from the basic concepts asdisclosed herein.

As an initial introduction, various respective aspects, modes,embodiments, variations, and features of the invention are herein shownand described, both broadly and in variously increasing levels ofdetail. Each provides individual benefit, either in its own regard, orin the ability to provide enhanced modes of operation and therapy by wayof combinations with other aspects or features. Moreover, their variouscombinations, either as specifically shown or apparent to one ofordinary skill, provide further benefits in providing useful healthcareto patients.

In one regard, two illustrative ultrasound spinal thermal therapy probeconfigurations are described for applying thermal (heat) therapy orultrasound (US) exposure to tissues within the spine or other joints.Heat at high temperatures and thermal doses can shrink tissues, changethe structural matrix, generate physiological changes and/or kill cells.Heat at relatively lower temperatures and US exposure can generatepermeability changes or changes in the cellular transport/metabolismthat increase effectiveness or deposition of certain pharmaceuticalagents. The heat or US can be delivered with the present invention in ahighly controlled fashion to selected tissue regions in order to exploitthese physiological effects for therapeutic purposes. Ultrasoundapplicators may achieve more precise targeting or heating control notpossible with current RF and Hot Source techniques. For soft tissue orbone surfaces within the spine or other joints, the high temperatureexposure can be used to shrink tissue impinging on nerves, re-structureand possibly strengthen mechanical properties of the disc or jointmaterial, destroy abnormal or undesirable cells or tissue, destroynerves responsible for pain, seal leaks from the disc annulus/nucleus,joint capsules, etc. Novel ultrasound applicators and treatmentmethodologies are thus herein shown and described which allow for theinterstitial insertion or laparoscopic or arthroscopic placement ofthese applicators within or upon targeted tissue to receive suchtreatments or prophylaxis.

As will be further developed by reference to the Figures below, oneexemplary type of such an applicator and treatment methodology providesa segmented array of tubular, sectored tubular, plate, hemispherical, orportions of cylinders (e.g. convex) with linear control of US exposureor heating via power level adjustments and angular control of USexposure or heating via directional characteristics of the applicators.(e.g. angularly directive with an inactive zone). These transducers aremounted over a guidewire lumen or tube or structure to facilitateplacement, wires, and/or cooling structures. Thermometry sensors can beplaced directly on the transducer/tissue or applicator/tissue interface.Internal cooling via gas or liquid or external cooling via an outerplastic sheath or catheter can be accomplished, though may not benecessary in many instances. These can be inserted within the disc orlaparoscopically placed against the target tissue or directed toward thetarget tissue. Acoustic gain and temperature regulation of applicatorsurface(s) can help control distance of heated regions and effects fromthe applicator surface. Frequency and depth of focus can be selected tocontrol heating pattern, and time can be varied to control heatingeffects and distribution. Some of the device and method embodimentsprovided herein may incorporate various features similar to thosepreviously disclosed such as in U.S. Pat. No. 5,620,479 to Diederich,though in many instances will be modified specifically for heatingwithin the special environment of use within or around intervertebraldiscs or other joints.

Another illustrative type of applicator according to the presentinvention incorporates a segmented array similar to that describedabove, but using concave sections of cylindrical or tubular transducersor spherical or semi-spherically focused transducers. The outer diameter(OD) of the tubes used to form such transducers are much larger than theapplicator diameter for the tubes—the sectors activated are a small arcof the tube they otherwise would be a part of. Thus, a line ofconvergence, e.g. focus, is produced at depth over a small arc angle,producing an intense US exposure or heating pattern which isapproximately the same length as the tubular segment transducer emittingthe US, though very narrow (e.g. 1-5 degrees) in the angular dimension.The length and number of segments can be varied in either applicatortype described here for introduction purposes (or elsewhere herein), andmay be a single transducer versus an array. These applicators can alsohave internal cooling or external cooling as described above and furtherdetail with respect to the particular embodiments below. The applicatorscan be inserted within the disc or laparoscopically placed against thetarget tissue or directed toward the target tissue. Acoustic gain andtemperature regulation of applicator surface can help control distanceof the heated region and effects from the applicator surface. Furtherapplicable features may by incorporated from other prior disclosures,such as U.S. Pat. No. 5,391,197 to Burdette et al. disclosing prostatetherapy devices and methods, and may be modified to suit the particularneeds for the present invention. Frequency and depth of focus can beselected to control heating pattern, and time can be varied to controlheating effects and distribution.

The various embodiments herein described have applications in other softand/or hard tissue sites and body parts where ultrasound exposure, hightemperature, low temperature, or combination effects are desired.

Each type of applicator can be designed with or without coolingballoons, distendable (e.g. compliant and/or elastomeric) or pre-shaped(e.g. substantially non-compliant with relatively fixed inflation sizeand shape), and symmetric or asymmetric shapes are considered. Thedevices' respective chasses may be substantially stiff, e.g. rigidprobes, or flexible. They may further be either implantable within thetarget tissue, or be used on surface contact. They may be delivered on aguidewire rail platform, through pre-shaped insertion or placementguides, or have their own steerability or deflectability. For spinaltreatments, they may be placed surgically following for example aposterior approach, or laparoscopic/arthroscopic lateral/anteriordirected to the spinal joint for treatment.

Treatment methodologies contemplated include implanting the deviceswithin or positioning them next to the target tissue for heating, suchas for example inserted into a disc or joint capsule, or placed outsideof the disc or joint.

Directivity and cooling aspects, when incorporated, protect sensitivenon-targeted tissue, which is highly beneficial for example in spinalapplications protecting spinal nerves. Applicators herein described arerepositionable according to various modes to control angular thermalprofile according to their directed energy delivery. In one example forfurther illustration, a specially adapted spinal disc insertionapparatus is adapted to deflect an applicator being deliveredtherethrough into the spinal disc from an angle. Other specialprocedures and tools are also herein described to align the applicatorswith target areas of tissue such as with respect to spinal joints andintervertebral discs in particular.

Though many different configurations, sizes, shapes, and dimensions arecontemplated consistent with the overall intent to meet the variousobjects of the invention, exemplary devices may be provided with outerdiameters between about 1.2 to about 3 mm, though may be up to 5 mm insome instances, deliverable as desired to spinal joint areas from 18gauge.

Insertion techniques into tissue to be treated may progress according toseveral examples. In one mode, a relatively stiff (e.g. sufficient tosupport the intended use), pre-shaped guidewire is used which may bewith or without memory metal alloy such as nickel titanium for example.The guidewire is inserted under fluoroscopy and positioned in an annulusfibrosus or posterior annulus, avoiding the nucleus of the disc. Anapplicator of the relatively more flexible variety is then inserted overthe guidewire and into position. In another regard, a relatively stiff(e.g. sufficient support) pre-shaped insertion tool guides theapplicator with a sharp tip into the annulus from outside withoutrequiring the guidewire (though they may be used in conjunction).Similar insertion techniques may be used for thermometry placement, ifdesired. Such delivery tool may thus be multi-lumened to integrate bothplacements (e.g. applicator and temperature probes) simultaneously forbetter positioning, etc.

Contact therapy techniques of operation may also proceed according to avariety of modes. An arthroscopic approach is suitable for manyapplications, such as for example as follows. Internal tip deflectionmay be used to align (e.g. steer) the applicator with or along theoutside of an annulus—e.g. similar to certain intracardiac catheters(such as mapping or ablation devices). Such may be integrated to asteerable catheter. The device according to these modes may be placedlateral or posterior behind the disc and nerves, or ventral. The deviceis aligned with the disc, the region is targeted and then treated withdirectional thermal therapy.

Various of the components herein described for the various embodimentsmay be provided together, or may be provided separately. For example,implements for providing streaming liquid or balloon to protect tissuefrom transducer conductive heating may be an integral part of therespective applicator, or may be separate as an accessory.

The applicators and respective insertion and/or guidance tools hereindescribed may be further adapted to be compatible with magneticresonance imaging for real time monitoring of the procedure. Otherimaging modalities may also be used for positioning, monitoring, thermalmonitoring, lesion assessment, real-time monitoring of coagulation, etc.This includes ultrasound monitoring.

Further to the ultrasound aspects of the various embodiments, use ofsuch energy modality provides temperature elevation as one mode ofcreating an intended effect, but also provides other non-thermal effectson tissues, such as for example drug activation, etc., such as forexample to treat arthritis at joints where the applicator is being used.

It is to be appreciated that the invention is in particular well adaptedfor use in treating intervertebral disc disorders of the spine, such asat spinal joints, and in particular at an intervertebral disc 1 shown invarious relation to surrounding spinal structures of a spinal joint inFIGS. 1A-2. In particular, as will be further developed below, discdisorders associated with chronic lower lumbar back pain are to bebeneficially treated according to the invention. However, it is to beappreciated that other disorders of the discs in particular, and ofother joints (e.g. hips, knees, shoulders, etc.) may also be treatedaccording to the device systems and methods herein shown and described.For example, other regions of the vertebrae will be beneficially treatedwith invasive ultrasound delivery according to the invention in order topromote bone growth, such as for example to assist in the healing ofinjuries or bone-grafts. Areas between the vertebral bodies, or thespinal processes, for example, may be treated with US application fromthe present devices and according to the methods as herein shown anddescribed. In particular, regions such as graft between inner bodiesthrough nucleus; anterior inner body fusion; posterior lateral fusionare contemplated. Ultrasound energy may be delivered with collagenmatrixes or autograft/allograft materials to bone.

A typical intervertebral disc 1 such as shown in FIGS. 1A-2 generallyincludes an annulus fibrosus 2 that surrounds a nucleus pulposus 3 alonga plane that lies between two adjacent vertebrae 8,9, respectively, thatare located above and below, also respectively, disc 1 along the spine.More specifically, disc 1 lies between two the two cartilaginousendplates 8 a,9 a that border two adjacent vertebral bodies 8 b,9 b ofvertebrae 8,9, respectively.

As will be further developed below, an ultrasound treatment deviceaccording to the invention may be located in various places in andaround a disc 1. A variety of such locations is shown for the purpose ofillustration at locations a-d in FIG. 1B, wherein device 11 is shown:within the middle of the nucleus at location a; along the border betweenthe nucleus 3 and the annulus 2 such as shown at proximal wall atlocation b; in the wall of the annulus itself, as shown for example atlocation c; or outside of the disc 1 around the outer periphery ofannulus 3, as shown at location d. Moreover, the device may also bedelivered into and around bony structures associated with the spinaljoint, such as for example shown at locations e, f, g, or h in FIG. 1B.Such positioning may be accomplished for example by drilling a bore intothe vertebral body from a posterolateral approach through an associatedpedicle, as shown in shadow at location E in FIG. 2, or via a morelateral approach as shown directly into the body at location F in FIG.2. Such positioning and heating within bone structures associated withthe joint may be in particular useful in one regard for treating bonecancer, destroying nociceptive nerves, stimulating growth or drug uptake(e.g. low thermal dose applications). Either the vertebral body itselfmay the target for heating, or the end plate, or the disc from suchlocation. A further particular useful application of this is treatmentof osteoporotic back pain.

As shown in particular in FIG. 2, disc 1 also has a shape similar to a“kidney”-shape with a concave curvature along a proximal wall 4 thatborders the spinal cord (not shown), as well as along opposite anteriorwall 5. Right and left anterior walls 6,7 are generally characterized bya more acute radius of curvature than posterior and anterior walls 4,5.As will be further developed below, each of these uniquely located andanatomical wall regions may be selectively treated with localizedtherapeutic ultrasound energy according to the system and method of thepresent invention. In general, intervertebral discs (with respect to thelumbar region associated with lower back pain) are typically 30 mm wide(e.g. laterally from right wall 6 to left lateral wall 7, about 20 mmfront-back, e.g. anterior wall 5 to posterior wall 4); and approximately10 mm tall, e.g. from end plate 8 a to endplate 9 a. Accordingly, thedevices herein shown and described are to be particularly adapted tooperate within this general description of the intended environment ofuse within intervertebral discs.

As will be appreciated by the description below of the various modes ofoperating the ultrasound treatment system of the invention, treatment ofthe annulus fibrosus 2 from within the nucleus may be achieved viavarious approaches. In particular, regions A and B shown in FIG. 2correspond to right and left anterior approaches, whereas regions C andD correspond to right and left posterior-lateral approaches around rightand left vertebral prostheses 8 c,8 d, respectively

Multiple ultrasound probe configurations are herein described forapplying thermal (heat) therapy or ultrasound (US) exposure to tissueswithin the spine in particular, though other joints such as knee, hip,etc. are contemplated. It is to be appreciated that the two specificprobe configurations shown and described provide highly beneficialembodiments, though they are exemplary and other configurations,improvements, or modifications according to one of ordinary skill basedupon this disclosure in view of the known art are contemplated.

In any event, heat produced according to the present invention at hightemperatures and thermal doses can shrink tissues, change the structuralmatrix, generate physiological changes, and/or kill cells within thetargeted region of tissue associated with a disc. Heat at lowtemperatures and US exposure can generate permeability changes orchanges in the cellular transport/metabolism that increase effectivenessor deposition of certain pharmaceutical agents. The heat or US can bedelivered with this technology in a highly controlled fashion toselected tissue regions in order to exploit these physiological effectsfor therapeutic purposes.

Ultrasound applicators may achieve a degree of precise targeting orheating control generally not possible with previously disclosed RF,plasma ion, or heat source techniques. In addition, ultrasound energyactually penetrates surrounding tissues, rather than according to othermodes (e.g. RF and laser) that heat the closest tissues the hottest andallowing conduction therefrom in a diminishing temperature profile curvewith distance away. For soft tissue or bone surfaces within the spine orother joints, high temperature exposure by use of the invention is usedto shrink tissue impinging on nerves, re-structure and possiblystrengthen mechanical properties of the disc or joint material, destroyabnormal or undesirable cells or tissue, destroy nerves responsible forpain, and seal leaks from the disc annulus/nucleus, joint capsules, etc.

In particular to disc applications, three general goals are intended tobe achieved according to use of the present invention: (1) collagenassociated with the annulus fibrosus may be reorganized to reshape theannulus; (2) nerve ingrowth in and around the annulus or nucleus may bekilled; or (3) inflammatory cells around areas of injury or otherwisepenetrating areas in or around a disc may be killed or ablated. Inparticular with respect to causing nerve damage, this may includeregions of the annulus itself, at the endplates, usually is locatedposteriorly, and rarely but at times may be within the region of thenucleus itself. In any event, such nervous ingrowth is typically relatedto structural disc damage that is identified e.g. in a discogram andtherefore predicted to be where pain/nerve treatment should be directed.

In one particular non-limiting application, either or both of nerve andinflammatory cells are necrosed by US delivery without achievingsufficient heating to denature or weaken, or to denature but not weaken,or to reshape the disc annulus. This is possible using the devices andmethods of the invention herein described at levels of energy deliverybetween about 10 to about 300 EM43 deg C. (e.g. may be from 1 to 60 minat between about 42 deg C. and about 45 deg C.). Where collagendenaturation, modification, or reshaping is desired, energy deliveryfrom the ultrasound devices herein described may be from between about55 deg C. to about 85 deg C. for between about 10 sec to about 30 min.

The novel ultrasound applicators and treatment methodologies hereindisclosed allow for the interstitial insertion or laparoscopic orarthroscopic placement of these applicators within or upon targetedtissue, in particular with respect to intervertebral discs.

One particularly beneficial embodiment of the invention is shown atultrasound treatment system 10 in FIGS. 3A-C. This system 10 includes anultrasound device 11, ultrasound drive system 40, and intervertebraldisc delivery assembly 50.

Device 11 is shown to couple proximally to an a proximal end portion(not shown) that generally includes a handle (not shown) that is adaptedto couple to ultrasound drive system 40, which includes an ultrasoundactuator 41. Drive system 40 may be operated empirically, such that apredetermined delivery of energy is achieved at a desired level known toproduce a desired result. Or, external therapy monitoring may beemployed during treatment, e.g. MRI, CT, fluoroscopy, X-ray, discogram,or PET in order to control energy delivery and determine appropriatelevels and time duration for a particular case. These monitoringmodalities may be effective prior to treatment in order to identify thearea of concern to be treated, which may impact the choice of particulardevice to be used as provided according to the embodiments herein. Stillin a further alternative embodiment, a treatment feedback device 42,such as a temperature monitoring system, may be incorporated in afeedback control system, as shown in FIG. 3A.

Device 11 is also adapted to be delivered to the desired location fortreatment through delivery assembly 50 and therefore has a lengthcorresponding to length L of delivery assembly 50 that is adapted foruse in standard access procedures for intervertebral disc repair. Forposterior-lateral approaches, such as for example in order to invade thenucleus 3 through posterior-lateral sites B or C shown in FIG. 2,delivery assembly 50 is typically a spinal needle of about 18 Gaugehaving a needle bore 53 and sharp pointed tip 51. Accordingly, thelength for device 11 may be about 30 cm long, with a corresponding outerdiameter for device 11 adapted to fit within such a needle, generallyless than about 3 mm, generally between about 1 and about 3 mm,typically between about 1.2 and 3 mm. However, other sizes may berealized for applications not requiring delivery through size-limitingdelivery assemblies such as spinal needles, and up to or greater than 5mm OD is realizable (e.g. in particular for applications outside of thedisc nucleus or within the annulus). For anterior delivery such as atsites A or B shown in FIG. 2, delivery assembly 50 may be minimallyinvasive delivery device such as an arthroscope or laparoscopicassembly.

Device 11 is of a type that contains a linear array of segmentedtransducers 16 that are adapted to provide selective, localizedultrasonic heating via radial, collimated energy delivery in tissueadjacent to the array. The particular device 11 of the presentinvention, including corresponding elements such as transducers 16located thereon, are generally smaller and more flexible than elsewherepreviously described for other linear array transducer devices. Inaddition, fewer transducers 16 are typically required for treating thegenerally smaller regions of the intervertebral discs as contemplatedherein. These substantial modifications are believed to significantlyenhance the controllability and performance of ultrasound therapy withinthe unique (and often dangerous) anatomy of an intervertebral disc.Otherwise, the basic components for segmented, linear array transducerdevice 11 may be similar to those previously described in U.S. Pat. No.5,620,479, which has been previously incorporated by reference above.

Referring more specifically to FIGS. 3A through 4, an ultrasoundapplicator 11 of the invention preferably includes a cylindrical supportmember such as a tube, conduit or catheter 12 which may be compatiblefor adjunctive radiation therapy of the spine such as according toremote afterloaders and standard brachytherapy technology. Sincecatheter 12 includes a coaxial longitudinal inner lumen 14, a source ofradiation, a drug or a coolant can be inserted therein, as well asguidewires, deflection members, stylets, etc., according to modifiedembodiments elsewhere herein described. One highly beneficial embodimentfor example uses a polyurethane or other similar polymer that is of asoft, low modulus type according to uses as contemplated herein withinthe sensitive intervertebral discs and elsewhere along the spine andrelated, highly sensitive nervous tissues. Where direct access to thedesired treatment location is possible without risk of damaging soft,sensitive tissues around the spine, a more rigid support may be used,and may even include a thin-walled stainless steel hypodermic tubing orstiff conduits (though shapes may be important as further developedbelow).

Catheter 12 is coaxially disposed through a plurality of tubularpiezoceramic transducers 16 which are spaced apart and electricallyisolated as shown, thus forming a segmented array of tubular ultrasoundtransducers which radiate acoustical energy in the radial dimension.Transducers 16 may be formed from a variety of materials as has beenpreviously disclosed. Transducers 16 may have an outer diameter betweenabout 0.5 to about 6 mm, though with respect to energy therapy fromwithin the nucleus 3, is more typically between about 0.5 mm and about1.5 mm.

It is preferred that the wall thickness for transducers 16 besubstantially uniform in order to generate uniform acoustic patternswhere such energy delivery is desired. Further to conjunctive radiationtherapy (e.g. spinal tumor therapy), the transducer material ispreferably stable when exposed to typical radiation sources.

The frequency range of the transducers will vary between approximately5-12 MHz depending upon the specific clinical needs, such as tolerableouter diameter, depth of heating, and inner catheter outer diameter.Inter-transducer spacing is preferably approximately 1 mm or less. Thoseskilled in the art will appreciate that, while three transducers 16 areshown in FIG. 3A-B, the number and length of transducers can be variedaccording to the overall desired heating length and spatial resolutionof the applicator and depth of penetration desired. This may vary forexample for devices 11 intended to treat along the entire length ofposterior wall 4 of disc annulus 2, versus a lateral wall 6,7 thereof,versus the anterior wall 5. Even the desired length along a given one ofthese regions may vary depending upon the particular patient, or evenwithin a given patient depending upon a particular region of the spinebeing treated (e.g. lower discs along the spine increase in size).Therefore, a kit of devices 11 having varied lengths and sizes for thearray of treatment transducers 16 is contemplated according to suchvariances. Transducers 16 are also shown to be substantially cylindricalfor the purpose of illustration, and which design may be desired whereuniform heating around the circumference of the device 11 is desired.However, as developed below, the highly selective tissue therapytypically desired within and around intervertebral discs may require inmany cases more radial selectivity around the device 11, as furtherdeveloped below.

Each transducer 16 is electrically connected to actuator 41 of driveassembly 40, which is typically an RF current supply. This electricallycoupling is achieved via separate pairs of signal carrying wires 18,such as 4-8 mil silver wire or the like, soldered directly to the edgesof the transducer surface to form connections 20 a,20 b. One wire in thepair is connected to the edge of transducer 16 at its outer surface,while the other is connected to the edge of transducer 16 at its innersurface, although other connection points and modalities are alsocontemplated. Each wire 18 is routed through the center of thetransducers between the outer wall of catheter 12 and the inner wall ofthe transducer 16, as can be seen in FIG. 3B, and from there to theconnection point through the spaces between the individual transducerelements.

In order to ensure that each transducer 16 in the array is kept centeredover catheter 12 while still maintaining flexibility and not impendingtransducer vibration, a plurality of spacers 22 are disposed between thetransducers and catheter 12. These spacers 22 may take various forms aspreviously described. For the particularly smaller designs hereincontemplated for spinal applications, a “spring-ground lead” comprising3-4 mil stainless steel wire or the like wound to form a coaxial springmay be placed between a transducer 16 and an electroded outer surface ofinner catheter 12 where such coil is soldered directly thereto. Suchelectroded outer surface may be a common ground for all transducers 16.

As previously disclosed, transducers 16 are preferably “air-backed” tothereby produce more energy and more even energy distribution radiallyoutwardly from device 11. To ensure such air-backing and that thetransducers 16 are electrically and mechanically isolated, aconventional sealant 24 as previously described is injected aroundexposed portions of catheter 12, wires 18, and spacers 22 betweentransducers 16. Sealant 24 serves multiple functions in thisapplication, as has been previously described.

As a means for monitoring temperature of tissue surrounding thetransducers 16, and to provide for temperature control and feedbackwhere desired, a plurality of small (e.g. 25.4 um) thermocouple sensors26, such as copper-constantan or constantan-maganin fine wire junctions,are placed along the outer surface of each transducer at points whichare approximately one-half of the length of the transducer, andconnected to individual temperature sensing wires 28 which run alongone-half of the length of the transducer 16 and then through the annularspace 36 between catheter 12 and the transducers 16. A conventionalacoustically compatible flexible epoxy 30 such as has been described isthen spread over the transducers, thereby embedding the temperaturesensors. The epoxy coated transducers are then sealed with an ultra thinwalled (e.g. about 0.5 to about 3 mil) tubing 32 that may for example bea heat shrink tubing such as polyester or the like. Or, the epoxy coatedtransducers may otherwise covered, as is known. Heat shrink tubing 32extends beyond the area over transducers 16 and covers substantially thelength of device 11 to distal end 38. To support tubing 32 in suchextended area, a filler 33 of chosen composition (preferably flexible)is placed around catheter 12 and between it and tubing 32.

According to the present embodiments and those elsewhere herein shownand described, a cooling system may be included, which has beencharacterized to increase heating efficiency by about 20-30% versusnon-cooled embodiments. In addition, as shown in FIG. 4, standoffs 34may be used to support transducers 16, which are preferably flexible andmay be an integral part of catheter 12.

For spinal disc therapies herein contemplated, device 11 is generallydesigned to be sufficiently flexible to be delivered in a substantiallystraight configuration through delivery device 50, and thereafter beadapted to assume a configuration appropriate for delivering energyalong a length corresponding to an interface between the linear array oftransducers 16 and the desired region of tissue to treat. Thisflexibility may be modified according to various different modeselsewhere herein described in order to achieve appropriate positioningand shape conformability used in a particular case.

In one particularly beneficial further embodiment shown variously inFIGS. 5A-B, device 11 is modified from the previous embodiment of FIGS.3A-4 such that inner support catheter, similar to catheter 12 in FIGS.3A-4, provides a through lumen 13 that is adapted to slideably receive aguidewire 60 therethrough. Guidewire 60 includes a stiff proximal endportion and either a shaped or shapeable, more flexible distal endportion 62. According to this guide wire-based embodiment for system 10,guidewire 60 is adapted to be placed within the desired region oftreatment by steering and advancing the shaped distal end portion 62with manipulation of proximal end portion 61 externally of a patient'sbody. Device 11 along the array of treatment transducers 16 issufficiently flexible to track over guidewire 60 in order to bepositioned for treatment along the desired treatment region. Guidewire60 may be of a shape memory type, or may be designed according to manyother previous guidewire disclosures. Moreover, device 11 may be adaptedto receive and track over guidewire 60 over substantially the length ofdevice 11, also known as “over-the-wire”, or may be of a “rapidexchange” or “monorail”-type wherein guidewire 60 exits proximally fromdevice 11 at a port along device 11 that is distal to the most proximalend of device 11.

FIG. 5A also shows the linear array of transducers 16 to be of thesegmented type, wherein each linear location for a transducer 16corresponds to two opposite transducer regions 16 a,16 b that may beindependently or alternatively actuated for energy delivery. This allowslocalization of US energy along only one radial aspect surroundingdevice 11. Particular designs and methods incorporating linear array ofsegmented or partially activated US transducer regions is disclosed inU.S. Pat. No. 5,733,315 to Burdette et al., which has been previouslyincorporated herein above. It is to be appreciated herein that eachtransducer segment 16 a or 16 b is in effect an independently actuatabletransducer, though shown and described as sub-parts of an overalltransducer 16 for illustrative simplicity. Corresponding transducerregions 16 a may be all actuated simultaneously along the array, withoutactuating the opposite regions 16 b, in order to ablate along a lengthonly along one radial aspect of device 11 corresponding to actuatedregions 16 a. Or, the other regions 16 b may be actuated without regions16 a emitting US energy. The device of FIG. 5A provides thisselectivity, which may be useful for treating different regions of adisc annulus as further discussed below.

Various different shaft structures may be appropriate for housing thecorresponding functional components of a device 11 according to theembodiment of FIG. 5A, though one particular cross-section is shown inFIG. 5B for illustration. Due to the radially segmented aspect of thetransducer array of this embodiment, the number of actuatable transducerelements corresponding to a given length of the array is doubledcompared to the earlier embodiment (e.g., each linear region is splitinto two radial regions). Therefore, twice the number of electrode leads18 and thermocouple leads 28 must be housed. The cross-sectioned,multi-lumen tubing 12A shown in FIG. 5B therefore has a plurality ofsurrounding lumens 14 surrounding a central guidewire lumen 13. This isadapted to give an organized shaft structure for adapting a proximal pinconnector to interface with drive and control system 40, as well asuniform flexibility in multiple planes to enhance delivery and positioncontrol in use.

Device 11 as illustrated by the FIG. 5A embodiment may includetransducers 16 having many different geometries that may be customizedfor a particular energy delivery profile along the transducer array.Examples include tubular (e.g. FIGS. 3A-4), sectored tubular (e.g. FIG.5A), and also as further examples planar or plate, hemispherical, orportions of cylinders (convex), depending upon the desired energydelivery for a particular application. Further to the FIG. 5Aembodiment, a distinct radial region of a transducer location along thearray may be rendered completely inoperative for US delivery, such asfor example in order to protect against delivery into sensitive tissuessuch as the spinal cord. In any event, according to the variousembodiments, device 11 may be adapted for linear control of US exposureor heating via power level adjustments and angular control of USexposure or heating via directional characteristics of transduceremitters 16 (e.g., angularly directive with an inactive zone).

A further embodiment shown in FIGS. 6A-C further providessemi-hemispherically shaped transducers 16 that are essentially flippedto have an opposite radial orientation relative to the radius of device11 as compared to otherwise similar transducer sectors 16 a,b in FIG.5A. More specifically, transducer segments 16 a,b each have theirconcave surfaces 17 facing outwardly from device 11. This is believed toallow for a focused US signal to be emitted therefrom to a focal pointor depth in relation to device 11 that is controlled by the radius ofcurvature R for the corresponding transducer. Such an arrangement mayinclude two radial sides of linearly spaced transducers, e.g. 16 a,b asshown in FIGS. 6A-B. Or, device 11 may be adapted to house a single suchtransducer segment 16, as shown in FIG. 6C, which limits the radialemission choices to one region around the device periphery, butincreases the design real estate and options for device 11 to house thisunique transducer configuration. In any event, the applicator device 11may be repositioned to control angular thermal profile. Where angularcontrol is of important necessity (such as treatment immediatelyadjacent spinal column), device 11 may be designed to be in particulartorqueable from outside the body in order to rotate the radially focusedtransmission with the shaft, such as via use of metal reinforcements ortubular members, or in general composite shaft designs such as wire orbraid reinforcements.

As elsewhere herein shown and described, device 11 along the US pathfrom transducer 16 generally includes an ultrasonically translucentmedium, such as a fluid. Acoustic gain and temperature regulation ofapplicator surface can help control distance of heated region andeffects from applicator surface. Frequency and depth of focus can beselected to control heating pattern, and time can be varied to controlheating effects and distribution.

The segmented array of FIG. 6C can use many different types oftransducers 16, such as for example concave sections of cylindrical ortubular transducers or spherical or semi-spherically focusedtransducers. The outer diameter of the tubes used to form the transducershown in FIG. 6C is much larger than the diameter for device 11 thatsupports the transducer 16. The transducer sectors are a small arc;thus, a line focus is produced at depth over a small arc angle,producing an intense US exposure or heating pattern which isapproximately the same length as the tubular segment, but very narrow inthe angular dimension, which can beneficially be as narrow as from about1 to about 10 deg., preferably as narrow as from about 1 deg. to about 5deg. The length and number of segments can be varied.

Referring to the particular embodiment shown in FIG. 6D, a conical orsemi-spherical disc-shaped transducer 16 is shown which focuses energynot only radially along a length of the corresponding transducer, butinstead focuses along the entire surface of the disc-shape. Thereforesuch shaped transducer more precisely and densely focuses and localizesthe energy being delivered into a very small region of tissue. While anarray of such shaped disc transducers 16 is contemplated, the focusedpattern may create energy gaps between adjacent elements—therefore thisdesign may be more applicable to precise treatment in one area by onetransducer, which may be followed by moving the transducer, eithertogether with or along the supporting device 11 to another location tobe treated.

As previously mentioned above, the embodiments of FIG. 6A-D, in additionto the other embodiments contemplated herein, can cooled eitherexternally or internally, an can be inserted within the disc orlaparoscopically placed against the target tissue or directed toward thetarget tissue. Acoustic gain and temperature regulation of applicatorsurface can help control distance of heated region and effects fromapplicator surface. Frequency and depth of focus can be selected tocontrol heating pattern, and time can be varied to control heatingeffects and distribution. Other examples of ultrasound array techniquesfor adjusting the selectivity of ultrasound transmission from a deviceare disclosed in U.S. Pat. No. 5,391,197, which has been previouslyincorporated by reference above; the various embodiments of thatdisclosure are contemplated in combination with this disclosure withrespect to segmented array of US transducers, where appropriate and asmodified according to this disclosure according to one of ordinaryskill.

As elsewhere provided herein, the illustrative embodiments andprocedures have applications in many different soft/hard tissue sitesand body parts where ultrasound exposure, high temperature, lowtemperature or combination of effects are desired. Joints in particularare locations where the present invention is well suited for providingtherapy. However, as stated above of particular benefit is use of thepresent invention for treating intervertebral discs.

Therefore, one example of a method for treating an intervertebral discaccording to the present invention is provided according to varioussequential modes of use shown in FIGS. 7A-F. This procedure for thepurpose of illustration more specifically shows posterior-lateralapproach to treating a posterior wall of an intervertebral disc from alocation within the nucleus. However, because selectivity in disctreatment is so very important, clearly other procedures arecontemplated as will be further developed through other examples below.

More specifically, according to FIG. 7A a posterior wall 4 of annulus 2is observed to require thermal treatment, either due to physical damageto the annulus 2 structure (e.g. herniation), or otherwise, such as forexample innervation with unwanted nervous tissue causing pain or otherinflammatory cells (which may be directly or indirectly related to discdamage such as herniation). As shown in FIG. 7A, a sharp, pointed tip 51of a spinal needle 50 is used in a posterior-lateral approach topuncture through the posterior-lateral region of the wall of annulus 2.This gives lumenal access through needle bore 53 into the nucleus 3 forultrasound probe delivery.

As shown in FIG. 7B, a guidewire 60 having a steerable distal tip 62 isthen advanced through needle bore 53 and into nucleus 3. It iscontemplated that guidewire 60 may be used for many purposes within thenucleus 3, or otherwise in or around disc 1. However, one particularlybeneficial use is shown, wherein guidewire is tracked along proximalwall 4, and then further around the more severe radius along lateralwall 7. This gives a rail along proximal wall 4 along which a highlyflexible device 11 may track for ablation there. This is shown in FIG.7C, wherein ultrasound transducers 16 are of length, size, and locationalong device 11 such that they are positioned over guidewire 60 tocoincide with the area along posterior wall 4 to be treated. Accordingto the embodiment shown in FIG. 7D, only one radial aspect of device 11is actuated for US emission and treatment, which is shown to betransducer segments 16 b in an array on one radial aspect of device 11interfaced with or facing proximal wall 4. Thus US energy is transmittedinto wall 4 to treat that region without substantial treatmentelsewhere.

After treatment, other regions may be treated by further manipulatingguidewire 60 and/or device 11 within the nucleus 3 (or outside ofannulus if desired). Once treatment within the annulus is completed,device 11 may be withdrawn. In the embodiments shown in FIGS. 7E-F, theultrasound transducers 16 may be used to assist in closing the woundformed at entry site C through annulus, such as by elevating thetemperature in that area sufficient to cause collagen shrinkage to aidin closing that aperture, as shown in FIG. 7F for example. In thisapplication, the entire circumference of device 11 may be activated forUS emission, or if only a radial region is adapted for such emission, itmay be rotated to heat all aspects of the wound aperture to seal it. Inaddition, a sealant may be administered through the distal end of device11 to close the wound, such as at introduction region C, either insteadof or in conjunction with ultrasonic emission from device 11.

Other regions of disc 1 may also require localized, selective therapywith US, and the present invention allows for highly specializedtreatments in the various regions. FIGS. 8 and 9 for example show use ofdevice 11 from the right posterior-lateral approach through site C shownin FIGS. 7A-F, but for treating anterior wall 5 and left lateral wall 7regions, respectively. For the embodiments shown wherein device 11 ishighly flexible for sufficient trackability over guidewire 60, the samedevice may be used for treating the very different areas shown in FIGS.7A-F, FIG. 8 (anterior wall), and FIG. 9 (left lateral wall). However,as shown in comparing FIGS. 7A-F, 8, and 9, different radial regions ofdevice 11 may be activated to treat the respective interfacing wall(where angular specificity is provided, which may not be required thoughoften preferred). In particular, the guidewire trackability of thepresent embodiments provides for highly beneficial flexibility betweenthe ability to treat these very different segments, in particular inview of the generally more significant curvature associated with theanatomy around the lateral wall regions as shown at radius R for lateralwall region 7 shown in FIG. 9.

For the purpose of further illustration, FIG. 10 shows a device 11according to the invention used to treat a posterior wall 4 of disc 1,but according to an anterior approach through a region of anterior wall5 adjacent to left lateral wall 7. Again, this may for example be asimilar device as that shown and described with respect to FIGS. 7A-9.

The devices and methods of the invention are also adapted for use intreating spinal disorders from outside of the annulus 2, thoughpreferably still from an invasive location within the patient's body inorder to provide the necessary and desired amounts of energy at only thehighly localized, target locations. For example, FIG. 11 shows a rightposterior-lateral approach to treat a region of annulus 2 from outsideof disc 1. Because of surrounding tissues, it is highly desired (thoughnot always required), to deliver only highly selective, directed USenergy into only the region of annulus 2 being treated. In particular,truncal nerves often extend along such areas, as well as the spinal cordbeing located not to far away from such region. Therefore, acontrollable, selective array of transducers as shown at transducers 16a radiates only toward the disc annulus 2, whereas the opposite side ofdevice 11 is non-emissive. In fact, this opposite side may beselectively cooled to prevent from thermal heating of the area, and mayinclude sensors to monitor such temperature around that area oppositethe active US treatment zone, such as for example at thermocouples 27shown in FIG. 11.

For the purpose of further illustration, FIG. 12 also shows US treatmentfrom outside of a disc 1 according to the invention, but according to ananterior approach. FIG. 13 shows still another exterior treatmentmodality, however this particular location along the posterior wall 4 isparticularly sensitive as the spinal cord is located immediatelyadjacent device 11 opposite transducers 16 a and must not be harmed.Therefore, not only the radial emission of energy (either US or thermalheat) from device 11 must be insulated from that radial regioncorresponding to the spinal cord.

Though guidewire tracking mechanisms provide the illustrativeembodiments for positioning in FIGS. 7A-13, other embodiments arecontemplated. Moreover, positioning of a device 11 may includesimultaneous or sequential positioning of thermometry probes formonitoring of sensitive tissue areas, etc.

A pre-shaped or otherwise directional introduction/delivery device mayassist to point a device 11 to a localized area for treatment, such asshown for example in shadow in FIG. 3A for shaped tip 51 for deliverydevice 50. Such directionality from the delivery device 50 may beprovided in addition to, or in the alternative to, providing guidewiretracking of device 11 or other additional positioning modes hereindiscussed. In addition, other positioning control mechanisms may beincorporated into device 11 itself as follows.

One particular deflectable tip design is shown for device 11 in FIG.14A-B. According to this embodiment, the region of device 11 thatincludes the array of transducers 16 is deflectable to take a variety ofshapes, such as shown in right and left deflection modes around a radiusr in FIG. 14B. Such deflection may be achieved using conventionaldeflection mechanisms, such as for example using an arrangement of oneor more pull-wires 55 integrated into the tip region so that tensioncauses catheter deflection. In addition, such deflection may be achievedinstead of along a length of an arc, around a pivot point, as shown inFIG. 14C. Such may be achieved in order to achieve different angles forsurgical approaches into the desired treatment areas, such as in oraround intervertebral discs. The transducer elements may be along adeflectable segment that is either round, or may be more planar asdesired.

Pre-shaped distal regions for device 11 may also provide for desiredtreatment of highly unique anatomies. A kit of devices, each having aparticular shape is contemplated. Such shapes may be integrated inprocedures with or without conjunctively using guidewire tracking. Forexample, FIG. 15A shows a pre-shaped distal end for device 11 having asimple distal curve around radius r. The transducers 16 are around theouter radius of such shaped end, and therefore this shape andorientation is suitable for example for treating an anterior wall 5 fromwithin a disc 1 via a posterior-lateral approach, such as for exampleaccording to FIG. 8. A similar shaped end is shown in FIG. 15B, but thetransducers 16 are instead on the inside radius r. This is more suitablefor posterior-lateral approach with posterior wall treatment, such asfor example in FIGS. 7A-F.

A further beneficial shape and orientation is shown in FIG. 16. Here, anacute bend shown around radius r2 is adapted to correspond to the moredrastically rounded lateral wall regions 6,7 of a disc annulus 2 with anenergy emission region on the outside of that bend. An additional bendregion may be highly beneficial, though not always required, shownproximally of the distal bend around radius r2 and having a less drasticbend, in the opposite direction of r2, shown around radius r2. Thisconfiguration is highly beneficial for treating lateral wall regions 6,7from a posterior-lateral approach (e.g. FIG. 9), though may be used inthe same configuration or slightly modified for anterior approach.

Though ultrasound transducers and their many benefits for invasiveenergy delivery into tissues has been extensively herein described,various of the embodiments further contemplate use with other energysources or treatment modalities, either instead of or in conjunctionwith ultrasound. Thus, treatment region 16 in FIG. 16 does notspecifically show individual ultrasound segments as in the otherfigures, for the purpose of illustrating other energy sources ortreatment modalities that my be incorporated thereon and still gain thebenefit of the unique shape provided for inner disc ablation accordingto that figure. Other sources such as electrical (e.g. RF), light (e.g.laser), microwave, or plasma ion may be used. In addition, cryotherapyor chemical delivery may be achieved along the regions variouslydesignated as “transducer 16”, which may be accompanied by othermodifications corresponding therewith, without departing from the scopecontemplated by the embodiments.

According to the various deflectable or pre-shaped modes, or modes whereenergy delivery is limited to only one side of the device, the device 11is preferably torqueable, such as by integrating into the shaft design acomposite of braided fibers or other stiff members. This allows for moreprecise control of the distal tip regions as it deflects or takes itsshape along a plane within the desired area of the body to treat.

The various embodiments for device 11 above may be adapted toincorporate active cooling, such as circulating cooling fluids within oraround active energy emitting elements such as transducers 16 variouslyshown or described. Such cooling may be integrated into the particulardevice 11, or may be achieved by interfacing the particular device 11inside of or otherwise with another device.

FIG. 17A shows for example device 11 within an outer jacket 15 that mayor may not be distendable, as shown in shadow at 15′. Outer jacket 15 isadapted to circulate fluids around transducers 16 and therefore isinterfaced with a circulation pump 70 in an overall system. In analternative embodiment sharing many common features as FIG. 17A, thedevice 11 shown in FIG. 17A provides for the cooling fluid to bedelivered through an interior passageway of the interior ultrasounddevice, out the distal tip thereof within the outer jacket 15, and backover the outer surface of the interior device including the transducers16.

In either the FIG. 17A or 17B embodiments, device 11 may be fixed withinouter jacket 15, or may be moveable relative to outer jacket 15, or visaversa. Fluids provided in an outer jacket surrounding transducers 16according to the invention may also be used beneficially for ultrasoundcoupling to intended tissues to be treated. This may be in addition toor instead of being used for cooling. In particular, such couplingfluids may be provided in a jacket 15 that is conformable, such thatirregular surfaces to be treated receive uniform energy coupling fromthe assembly. Or, pre-shaped, and symmetric or asymmetric shapes, may beprovided as appropriate to provide such coupling. Ultrasound couplingmay be further achieved by providing a non-liquid coupling member as astand-off over a transducer in order to couple that transducer to thetissue—such as for example a sonolucent coupling gel pad, etc.

In addition to the various designs for device 11 described above forachieving positioning, e.g. guidewire tracking, pre-shaped, ordeflectable, other mechanisms may also be incorporated for accuratepositioning. For example, stiff or flexible distendable member(s) may beincorporated on device 11, e.g. a balloon or expandable cage, thatdistends to a predetermined-shaped (or just generally distends). Thismay help positioning, such as for example where the nucleus 3 is void ofpulposus in order to position the transducers 16 within a balloon at adesired location within the annulus 2. In addition to positioning, sucha member may also be used to aid coupling, tissue deforming, and tissuerepositioning during a treatment procedure.

As previously discussed, the intervertebral disc applications ofultrasound herein contemplated require high selectivity for US orotherwise thermal therapy due to the presence of highly sensitive,non-targeted tissues in close proximity (e.g. spinal cord and othernerves). Therefore, though heat conduction may not be the intended modeof therapy with transducers 16, their concomitant heating during USsonic wave delivery may cause unwanted damage in either the targeted ornon-targeted tissues. Accordingly, cooled lumens or balloons over thetransducers may be employed to protect such tissues from such heat, ordirectivity of the ultrasound per the embodiments herein described myadequately protect sensitive non-targeted tissue. In the case of anactive cooling mechanism, it is to be appreciated that such mechanismmay be integrated directly onto device 11 that carries the transducers16. Or, a separate co-operating device such as an outer sleeve carryingcooling fluids may be used. Such cooling chamber may be on the side ofthe transducer delivering the targeted US wave, in which case fluid inthe chamber must be substantially sonolucent for efficient energydelivery. In the event the cooling is intended to protect a “back side”of the device only, other fluids may be used.

Applicators, such as the various embodiments shown for device 11 amongthe FIGS., and insertion tools, e.g. delivery device 50, may be adaptedto be MR compatible for real time monitoring of a particular procedure.Also other imaging modalities may be used instead, or in conjunctionwith one another, in order to control and optimize the US treatmentprocedure, including for example for monitoring positioning,temperature, lesion assessment, coagulation, or otherwise changes intissue structures related to the treatment (e.g. targeted tissue to beheated or adjacent tissues to monitor safety, such as regions of concernto preserve nerves associated with the spinal cord). In fact, US itselfis an energy source that has been widely used for acoustic imaging inand around internal body structures. It is contemplated that imaging USdevices may be incorporated into a device 11 directly, or indirectlyincorporated as a separate cooperating device in system 10, and furtherthat the US treatment transducers 16 herein shown and described may beoperated in imaging modes before, during, or after thermal US therapy isperformed with those same transducers 16.

In addition to the spine, the device systems and methods according tothe embodiments may be used in other regions of the body, in particularother joints. Examples of such regions include knee, ankle, hip,shoulder, elbow, wrist, knuckles, spinal processes, etc. In such case,further modifications from the illustrative embodiments herein providedmay be made in order to accommodate the unique anatomy and target tissueregions, without departing from the spirit and scope of the presentinvention.

While the device systems and methods have been herein described withrespect to treating tissue via US exposure in order to providehyperthermia effects, other non-thermal results may also be intended,either in conjunction with hyperthermia or in the alternative to. Forexample, drug activation and or enhanced drug delivery, such as forexample via enhanced dispersion or cellular permeability or uptake, maybe achieved by delivering certain specific therapeutic dosing of USenergy, as has been well studied and characterized in the art. Suchmethods may for example aid in the treatment for example of arthritis injoints, etc.

The invention as described herein according to the particularembodiments is highly beneficial for treatment of the body, inparticular joints, and in particular the spine. In general, thesedevices and methods are adapted for such treatment invasively fromwithin the body. However, external applications are contemplated aswell. In addition, treating living bodies according to the invention isbelieved to provide a highly therapeutic result for improved living.Nevertheless, use of the devices and methods as described herein arealso contemplated for conducting scientific studies, in particular withrespect to characterizing tissues in their relation to applied energy.Therefore, “therapeutic” applications may include those sufficient toinduce a measurable change in tissue structure or function, whetherliving or post-mortem, prophylactic or ameliorative, research orclinical applications.

EXAMPLE External Directional Ultrasound Thermal Therapy of CadaverSpinal Discs

FIG. 18A shows an X-ray photograph of a cadaver intervertebral discduring invasive ultrasound treatment with a device and method accordingto the invention as follows. Temperature monitoring measurements areshown as overlay dotted lines and numbers over the X-ray.

An ultrasound probe was provided as follows. Two PZT ultrasoundtransducers were provided on a hypotube, each being 1.5 mm OD×10 mm long(0.012″ wall thickness), and being spaced by about 1 mm. The ultrasoundprobe was inserted within a 13-g Brachytherapy Implant Catheter having a2.4 mm O.D., which is commercially available from Best Industries. Waterat room temperature was circulated through the outer catheter and overthe transducers at about 40 ml/min during ultrasound transmission. Theassembly of the outer catheter with inner transducers and probe wasinserted laterally into a cadaver disc along the border of the nucleuspulposus and posterior wall of the annulus fibrosus. The approximatelocation of the transducers is shown in two rectangles in FIG. 18A.Thermocouple probes were inserted into the disc as shown in the X-ray,and with measurement locations reflected by the sample measurements inthe overlay. The above test sample and instrumentation was placed withina 37 deg C. water bath during testing. Each transducer was run atapproximately 10 W power, wherein temperature numbers shown in FIG. 18Agenerally represent temperatures at substantially steady state afteractuating the transducers. Heat generated by the ultrasound probe wassufficient to cause therapeutic effects in surrounding tissues of theannulus and nucleus.

Another similar study was performed using ultrasound to heat apost-mortem intervertebral cadaver disc using a curvilinear ultrasoundapplicator directly coupled to tissue at 5.4 MHz and 10 W power. Atemperature vs. time graph of the results at varied depths from thetransducer surface are shown in FIG. 18B, which shows among otherinformation that temperatures reached 70-85 degrees within 7 mm from thedisc treatment surface and within 5 minutes of treatment.

As shown in the graph of FIG. 18B, the elevated temperature achieved at1 mm from the ultrasound transducer reached: over 45 degrees C. within90 seconds (1½ minutes); over 70 degrees C. within 120 seconds (2minutes); over 75 degrees C. in nearly 120 seconds; over 80 degrees C.within 180 seconds (3 minutes); and over 85 degrees C. by about 300seconds (5 minutes).

Temperatures at 4 mm depth from the transducer reached: 45 degrees C. inless than 120 seconds (2 minutes); 55 degrees in close to about 120seconds; 65 degrees C. within 150 seconds (2½ minutes); over 70 degreesC. within less than 210 seconds (3½ minutes); and over 75 degrees C. andstill rising by about 240 seconds (4 minutes).

Temperatures at 7 mm depth from the transducer reached: 45 degrees C. byabout 120 seconds (2 minutes); 55 degrees C. by about 150 seconds (2½minutes); 60 degrees C. in nearly 180 seconds (3 minutes); 65 degrees C.within 240 seconds (4 minutes); and 70 degrees C. within 300 seconds (5minutes).

Temperatures at 10 mm depth from the transducer reached: 45 degrees C.in less than 150 seconds (2½ minutes); 55 degrees C. in less than about210 seconds (3½ minutes); over 60 degrees C. in less than 270 seconds(4½ minutes); and slightly less than about 65 degrees C. by 300 seconds(5 minutes).

In another regard, the graph in FIG. 18B also shows that temperaturesabove 45 degrees C. were reached within 90 seconds at 1 mm, 120 secondsat 4 mm and 7 mm, and 150 seconds at 10 mm depths from the transducer.Similarly, temperatures of at least 55 degrees C. were reached withinabout 120 seconds at 1 mm and 4 mm, 150 seconds at 7 mm, and 210 secondsat 10 mm depths. Temperatures of at least 65 degrees C. were reachedwithin less than 120 seconds at 1 mm, 150 seconds at 4 mm, 240 secondsat 7 mm depths. Still further, temperatures above 70 degrees C. werereached within 120 seconds at 1 mm, 210 seconds at 4 mm, and 300 secondsat 7 mm depths. Even further heating to above 75 degrees C. were reachedwithin close to 120 seconds at 1 mm, and 240 seconds at 4 mm depths.

Further observation of FIG. 18B in the time domain, in less than 150seconds temperatures at up to 7 mm depth from the transducer reached atleast 55 degrees C. Within about 210 seconds temperatures in tissue asdeep as 4 mm deep reached over 70 degrees C., up to 7 mm deep reached atleast 60 degrees C., and up to 10 mm deep reached over 55 degrees C.Within 270 seconds, temperatures 4 mm deep reached over 75 degrees C.,up to 7 mm deep reached over 65 degrees C., and up to 10 mm deep reachedover 60 degrees C. In still a further regard, by 300 secondstemperatures up to 7 mm deep reached at least 70 degrees C., and up to10 mm deep reached almost 65 degrees C.

Upon further comparison of temperatures vs. depth according to the FIG.18B graph: temperatures over 60 degrees C. (and for the most part up to65 degrees or more) were achievable up to 10 mm deep; temperatures up toat least 70 degrees C. were achieved up to 7 mm deep; temperatures over75 degrees were achieved up to at least 4 mm deep; and at 1 mm depthtemperatures of over 80 degrees and even 85 degrees were observed.

As will be further developed below and elsewhere herein, such elevatedheating, including at tissues as deep as 4 mm, 7 mm, and in some regardseven 10 mm, is a highly beneficial aspect of the present invention. Forexample, other more conventional intervertebral disc heating devices, inparticular the “IDTT” device elsewhere herein described, have beenobserved to be limited as to the extent and depth of heating possible.

For example, according to at least one study observing the heatingeffects of the “IDTT” radiofrequency electrical heating device(elsewhere herein described) also on cadaveric lumbar spine discsamples, the following observations were made. During intended modes ofuse for internal disc heating, and over treatment times of 17 minutes(1020 seconds), the IDTT devices tested were able to heat only theclosest 1-2 mm of intervertebral disc tissue to temperatures just barelyexceeding 60 degrees, with no tissue of 1 mm depth or greater exceeding65 degrees C. despite reaching 90 degrees C. on the probe itself.Moreover, only tissues within a 7 mm radius of the heating probeexceeded 48 degrees C. during the 17 minute treatment time. Stillfurther thermal dosing was limited such that the maximum predicted depthfor damaging nociceptive fibers infiltrating the discs was believed tobe only within a 6-7 mm radius.

Accordingly, substantial benefit is gained by using the ultrasoundtreatment device of the present invention to the extent depth of heatingand heating to substantial temperatures and within reasonable times isdesired.

EXAMPLE Thermal Therapy of Pre-Stressed Spinal Joints

This Example provides an abstract summary, introduction, methods,results, and conclusions with respect to a certain group of studiesperformed to evaluate heat-induced changes observed in intervertebraldiscs, related structures such as in particular annulus fibrosus, andthe related biomechanics, in particular with respect to “intact” discs,as follows.

1. Abstract.

The intervertebral disc is considered a principal pain generator for asubstantial number of patients with low back pain. Thermal therapy hasbeen disclosed to have a healing effect on other collagenous tissues,and has been incorporated into various minimally invasive treatmentsintended to treat back pain. Since the therapeutic mechanisms of thermaltherapy have generally been previously unknown, proper dosage andpatient selection has been difficult. Thermal therapy in one regard hasbeen disclosed to acutely kill cells and denature and de-innervatetissue, leading to a healing response.

The purpose of this study was to quantify the acute biomechanicalchanges to the intact annulus fibrosus after treatment at a range ofthermal exposures and to correlate these results with the denaturationof annular tissue. Intact annulus fibrosus from porcine lumbar spineswas tested ex vivo. Changes in biomechanical properties, microstructure,denaturation temperature, and enthalpy of denaturation before and afterhydrothermal heat treatment (at 37, 50, 60, 65, 70, 75, 80, and 85° C.)were determined. Shrinkage of excised annular tissue was also measuredafter treatment at 85° C. Significant biomechanical changes in theintact annulus were observed after treatment at 70° C. and above, butthe effects were much smaller in magnitude than those observed inexcised tissues. Histological and mDSC data indicated that denaturationhad occurred in intact annular tissue treated to 85° C. for 15 minutes,though such effect was observed to be slight. It is believed based onobservations made that constraints imposed on the tissue by the jointstructure retard changes in properties. These findings have implicationsfor dosing regimens when thermally treating disc tissue.

2. Introduction.

The goals of this study were to: 1) quantify acute biomechanical changesto the intact annulus fibrosus induced by a broad range of ex vivothermal exposures; and 2) to correlate these results with denaturationof annular tissue using modulated differential scanning calorimetry(mDSC) and histological data.

3. Methods.

a. Mechanical Testing.

Forty-one spinal motion segments (18 L₁₂, 19 L₃₄, 19 L₅₆) consisting ofthe intervertebral disc (IVD) and each adjacent vertebral body were cutfrom 22 fresh frozen porcine lumbar spines (domestic farm pig weightrange: 115-135 lbs). Muscular and ligamentous structures, facet joints,transverse processes, and posterior elements were dissected from thevertebral bodies to isolate the disc. Saline-soaked gauze was wrappedaround the discs during preparation to minimize dehydration. Next, thenucleus was depressurized by drilling holes first through the vertebralbodies to the center of the nucleus in the superior-inferior direction,and then from the anterior faces of the vertebral bodies to the centralhole. Plastic tubing was inserted into the anterior openings and affixedwith cyanoacrylate. The vertebral bodies, anchored with 2.5 mm threadedrod, were embedded into fixation cups using polymethylmethacrylate(PMMA). An alignment bar mated with grooves in the fixation cups toensure that the plane of the disc remained normal to the verticalloading axis. X-rays (Faxitron Cabinet X-Ray System, Hewlett-Packard,McMinnville, Oreg.) were taken of the specimens in the dorsal-ventralplane after equilibration in a 37° C. saline bath. Disc heights weredetermined by averaging three caliper readings from the dorsal-ventralx-rays.

Specimens were secured in fixation cups, mounted into a hydraulicmaterials testing machine (MTS Bionix 858, Eden Prairie, Minn.), andplaced into a temperature controlled 0.15M saline bath at 37° C. toequilibrate. Saline at bath temperature was also circulated through thecenter of the discs via the tubing attached to the vertebral bodies;this allowed for a more rapid and uniform heat distribution within theannulus.

Temperatures were measured using two stainless steel thermocouple needleprobes, one placed in the bath, and one inserted approximately halfwayinto the anterior annular wall. These fine-needle temperature probeswere fabricated in-house using 25 micron constantan-manganinthermocouple junctions embedded within a 30 gauge (0.30 mm OD) needle.Superior-inferior x-rays were used to verify proper placement of theannular temperature probe.

The testing protocol consisted of a 20-minute thermal equilibration at37° C., a 15-minute heat treatment, and another 20-minute equilibrationat 37° C. Fast temperature changes were facilitated by exchanging thesaline in the bath with that in a reservoir heated to the desiredtemperature and then maintained with temperature-controlled circulation.The target temperature (to within 7%) was reached within 5 minutes ofexchanging the saline. During the equilibrations, the disc stress wasmaintained at 0 kPa.

Mechanical testing was performed at 37° C. just prior to heat treatmentand again subsequent to heat treatment and re-equilibration at 37° C.Testing consisted of nine preconditioning cycles in axialtension-compression (−25 to +150N at 0.25 Hz), followed by one testingcycle to the same limits. The applied load was measured using aprecision force transducer (Load Cell 662, MTS, Eden Prairie, Minn.),and the deformation of the disc was assumed to be the change in distancebetween fixtures, measured using the test system LVDT. Data wascollected every 0.01 seconds during mechanical testing and every 15seconds during heat treatment and equilibration. Heat treatment was toone of the following temperatures: 37 (Controls), 50, 60, 65, 70, 75,80, or 85° C. Five specimens were tested at each treatment temperatureexcept for the 60° C. group that had six specimens.

After testing, specimens were removed and the discs were cut in thetransverse plane and scanned at a resolution of 600 dpi (CanoScan N656U,Canon, Inc., Costa Mesa, Calif.). Annulus areas were measured usingimaging software (Scion Image, v. 4.0.2B, Frederick, Md.).

Two additional experiments were conducted to allow us to explore thelimits of annular thermal response. In the first study, a specimen wasprepared as described above and treated at 85° C. until the thermalcontraction stabilized (within 0.01 mm). For the second study, sectionsof anterolateral annulus were excised from five lumbar discs (2 L₂₃, 3L₄₅) from four different spines and treated at 85° C. using the sameheating protocol as above. X-rays were taken before and after treatment,and changes in circumferential and radial dimensions after heattreatment were measured using digital calipers.

b. Microstructure

Tissue samples were excised from 37° C. and 85° C. mechanical testspecimens, and from an excised specimen treated at 85° C. Samples wereembedded in paraffin, sectioned in the circumferential plane at 6microns, and stained with HBQ (Hall, 1986). The sections were imaged ona Nikon Eclipse E800 microscope (Nikon, Melville, N.Y.) under brightfield to examine tissue structure, and under polarized light to assesscollagen birefringence.

c. Modulated Differential Scanning Calorimetry

Traditional DSC measures the combined effects of reversible andnonreversible heat flow, but the two components can be measuredseparately if the modulated DSC (mDSC) technique is used. mDSC wasperformed on samples of anterolateral annulus fibrosus removed fromfifteen previously treated specimens (Cambridge Polymer Group,Somerville, Mass.). Punches (approximately 10 mg) were removed from thecontrol (37° C.) mechanical test specimens (n=5), mechanical testspecimens treated at 85° C. (n=5), and from the excised annularspecimens treated at 85° C. (n=5). Each sample was placed in 0.1% NaClsolution for 20 minutes, blotted, weighed, and crimped into an aluminumanodized hermetic DSC pan. Samples were placed into a Q1000 differentialscanning calorimeter (TA Instruments, New Castle, Del.), equilibrated at55° C., and then ramped from 55° C. to 95° C. at 0.5° C./min. Using anempty pan as a reference, total enthalpy of denaturation (EH) and thetemperature corresponding to the nonreversible endothermic peak (T_(m))were recorded. Following the mDSC procedure, samples were vacuumdehydrated, and the fractional dry mass (ratio of dry weight to wetweight) was recorded.

4. Data Analysis

The force and displacement data from the mechanical tests were convertedto stress and strain. The stress and strain data for each mechanicaltest were then fit to a high-order polynomial, and an equation for thespecimen tangent modulus was calculated as the derivative of thispolynomial. A plot of modulus vs. applied stress was constructed. Thestress at the inflection point—the transition between tension andcompression—was the stress at which the second derivative of thepolynomial was zero. The reference configuration was defined as thestress and strain at the pre-treatment inflection point. Threebiomechanical parameters were calculated from the modulus vs. appliedstress curves to quantify heat-induced changes in the mechanicalresponse (FIG. 19): the change in modulus at the inflection point (MI),the change in modulus at 150 kPa (M150), and the change in residualstress at inflection point (RSI). The percent change in hysteresis (HYST%) was calculated from the pre- and post-treatment load-displacementcurves. The change in the modulus at the inflection point is a measureof the increase or decrease in the stability of the joint, while thechange in the modulus at 150 kPa is an indication of how well the jointwill withstand physiologic loading. The percent change in strain at 0stress (E0%) was used to quantify axial shrinkage of the tissue.

Differences in each parameter with treatment temperature were comparedusing a one-way analysis of variance (ANOVA). Post-hoc multiple pairwisecomparison tests (Fisher's Least Significant Difference) were performedto determine differences between treatment groups with a significance ofp<0.05.

5. Results.

a. Mechanical Testing

FIG. 21 includes various graphs representing observed biomechanicalparameters after varied heat treatments according to the present studyas follows: graph (a) represents change in modulus at the inflectionpoint (MI); graph (b) represents change in modulus at 150 kPa (M150),graph (c) represents percent change in strain at 0 stress (E0%), graph(d) represents change in residual stress at the inflection point (RSI),and graph (e) shows percent change in hysteresis (HYST %). Further tothe graphs in FIG. 21, the reference letter “X” is used to designatewhere data is significantly different from 37° C. group, p<0.05; whereasthe symbol “+” is used to designate where data is observed to besignificantly different from the 85° C. group, p<0.05.

Significant differences between the control group and the heat-treatedspecimens were observed at temperatures of 70° C. and above (FIGS. 19,20, 21). The variation increased with increasing treatment temperature.No significant changes were observed between the control group and the50 and 60° C. groups, and the 65° C. treatment group showed a changeonly in the hysteresis parameter. The modulus at the inflection point(MI) increased by 152 kPa after treatment at 70° C. (p<0.05), andcontinued to increase with increasing heat treatment: the 85° C. group,with an average increase of 343 kPa after treatment as shown in FIG.19), and was significantly different from both the control group(p<0.001) and the 70° C. group (p<0.05) according to the graph in FIG.21a . The modulus at 150 kPa (M150) significantly decreased for groupstreated at 70° C. and up, but did not continue to decrease withincreasing treatment temperature; the decrease was 17% at 70° C. and 18%at 85° C. as shown in the graphs of FIGS. 19, 21 b.

Relative to the control group, significant axial shrinkage (E0%) wasfirst observed at the 70° C. treatment temperature. There was nosignificant difference observed in this particular experiment betweenthe axial shrinkage after treatment at 70 and 85° C., although there wasa trend towards continued increase (p<0.10) according to the graphicalresults in FIG. 21c . The change in the residual stress at theinflection point (RSI) after heat treatment was significantly larger forgroups treated at temperatures of 75° C. and up with a trend towardsincreasing stress with increasing treatment temperature (75 vs. 85° C.,p=0.084), as shown in the graph of FIG. 21d . A 36% percent increase inhysteresis (HYST %) was observed for the 65° C. group; this wassignificantly larger than that of the control group (p<0.05) per theFIG. 21e graph.

The disc heights of the specimen exposed to long heat treatment time at85° C. stabilized after approximately 2.5 hours. As a result oftreatment, M150decreased 47%, MI increased 625 kPa, RSI was 47.3 kPa,and hysteresis increased 98%. The percent change in strain at 0 stress(E0%) was 22.5%.

Heat treatment of the excised annulus at 85° C. resulted in shrinkage of45.1%±5.5% in the circumferential direction and expansion of 56.9%±25.4%in the radial direction. The shrinkage was accompanied by a color changefrom white to translucent, a finding that which was not present in ourwhole-disc samples.

b. Microstructure

The structure of the annular collagen, as indicated by its birefringenceunder polarized light microscopy, varied with heat treatment (FIGS.22a-f ). The structure of the excised sample treated at 85° C. changeddramatically relative to that of the control specimen: the 37° C.specimen was strongly birefringent under polarized light as shown inFIG. 22b , while the 85° C. excised specimen showed no birefringence asshown in FIG. 22f . The 85° C. mechanical test specimen appeared lessbirefringent than the control, as shown in FIG. 22d . Bright lightmicroscopy revealed a structure consistent with that observed underpolarized light. The heated excised specimen exhibited a homogenousmorphology, as shown in FIG. 22e , with a complete loss of the originalstructure relative to the control shown in FIG. 22a . Tissueorganization decreased, but was not absent, in the 85° C. mechanicaltest specimen shown in FIG. 22 c.

c. Modulated Differential Scanning Calorimetry

The excised specimens did not exhibit an endothermic peak, and thus,values for T_(m) and ΔH were not calculable. Both intact groupsexhibited a full and clear endothermic denaturation event. There were nosignificant differences in T_(m) and ΔH between the intact (37° C. & 85°C.) specimens. T_(m) for the control group and the 85° C. intact groupwere 65.4±1.5° C. and 65.3±0.9° C. respectively, while ΔH was 11.5±2.4W/g and 12.2±4.6 W/g. The fractional dry mass of the 85° C. intact group(0.33±0.03) and the 85° C. excised group (0.37±0.043) were bothsignificantly higher than the control group (0.26±0.04; p<0.05 andp<0.01, respectively).

6. Discussion

In this study we examined the acute biomechanical effects of thermaltreatment on the annulus fibrosus. The data demonstrate that treatmentfor 15 minutes at 70° C. or above is required to produce statisticallysignificant biomechanical modification of the intact motion segment exvivo. Heat treatments of 70° C. and higher resulted in stiffening of theannulus at low loads (i.e. in the ‘toe’ region, parameter MI) and adecrease in stiffness at higher applied loads (M150).

These results suggest that thermal therapy at temperatures 70° C. andgreater leads to a more stable transition from flexion to extension. Thedepressurization we performed during specimen preparation created aneutral zone at the transition between tension and compression, withinwhich small changes in force resulted in relatively large changes indisplacement. After treatment at higher temperatures, this neutral zonewas reduced or eliminated, as reflected in the graph shown in FIG. 20.It is further believed that the experimental model was illustrative of,and that this response would similarly affect, the neutral zone ofintact discs. By contrast, our observation that heat treatment attemperatures greater than 70° C. softens the annulus at higher forcessuggests that the acutely treated intact disc may be at increased riskof injury when brought to its range-of-motion limits. This confirms, inthe unique setting of vertebral discs, similar behavior that has beennoted in the shoulder capsule, where heat has been observed to bothacutely shrink and decrease the linear-region stiffness of the joint. Asa result of such prior observations in that setting, clinicalpractitioners have recommended joint protection for six to twelve weeksafter treatment.

While the trends in our data are comparable to those reported for othertissues such as the shoulder capsule, the magnitude of the annulartreatment effect in intact tissue is smaller. For instance, whileshoulder capsule contraction has been reported in at least one study tobe 60% after 80° C. treatment, we observed annular contraction of only7.8% (E0%) after heating the intact disc to 85° C. Similarly, shouldercapsule stiffness reductions at high loads were much greater than thoseobserved in the intact vertebral discs: we observed stiffness decreasesof 20% (M150), while shoulder capsule stiffness decreases were on theorder of 50%. It is believed that these differences are likely due toeither the unique joint structure or the fiber orientation of the intactannulus, or both. The shoulder data was derived from experiments inwhich the capsule, a linearly oriented collagenous tissue, was cut intostrips along the collagen fiber direction before testing. In contrast,intact annular collagen is oriented in two directions at ±65° to thespinal axis, and it is highly constrained both axially, by the adjacentvertebrae, and circumferentially, by its annular structure. When the insitu constraints on the annulus were removed by excising the tissuebefore heat treatment, we observed a 45% circumferential shrinkage,which is similar in magnitude to that reported for linear collagenoustissues. It is believed, therefore, based upon our observations, that insitu tissue constraint, rather than fiber orientation, may be thedominant mechanism responsible for the observed differences.

Our conclusion that in situ tissue constraint reduces the effects ofthermal therapy on the annulus fibrosus, though not previously known orconfirmed prior to this study, is further supported by results observedin several other previously reported studies. In one previous report,for example, only 6.6% shrinkage was observed in the patellar tendon, alinearly oriented collagenous tissue, after in situ treatment with laserenergy. This difference was attributed to constraints imposed by theintact joint. Similarly, a number of other studies have been reportedexamining heat-induced changes in the mechanics of chordae tendineae.Tissue stress was observed to have a retarding effect: when tissue wasstressed during heating, increases in the temperature, the heating time,or both, were required to achieve effects noted for unstressed tissue inthese studies.

The mechanism by which tissue stress retards thermal denaturation has athermodynamic basis. Tensile stress straightens tissue collagen anddecreases configurational entropy, which in turn, increases theactivation energy required for thermal denaturation. This retardingeffect was clearly evident in intact annulus, where we observed thatseveral hours of thermal treatment at 85° C. were required to achievemaximum contraction. In contrast, at least two groups of priorresearchers examining excised collagenous tissues achieved maximumcontraction within 5 minutes. Also, while M150 for an intact specimentreated at 85° C. for 15 minutes was only 18%, the decrease in stiffness(47%) after several hours of treatment at 85° C. was comparable to thatelsewhere reported for excised shoulder capsule tissue.

Our polarized light microscopy data provides further evidence thattissue constraint effects both the temperature and time required toachieve a given amount of thermal damage. Collagen birefringencedisappeared completely after heat treatment for 15 minutes at 85° C. inthe unconstrained specimen, but it remained in the intact treatedannulus. Clearly 15 minutes of treatment was not sufficient to fullydenature the intact annular tissue. While it was not possible toquantify the degree of birefringence in the intact tissue aftertreatment at 85° C. relative to that at 37° C. with only one specimen,it appears that that the treated specimen was less birefringent than thecontrol. These observations are consistent with the results of ourmechanical tests.

Differences in the mechanical behavior of the intact annulus aftertreatment at temperatures greater than 70° C. indicate that the tissueunderwent a thermally mediated change. However the results of the mDSCexperiments indicate that tissue constraint prevented significantcollagen denaturation: the main denaturation peak and enthalpy ofdenaturation of the intact annulus were unaffected by 15 minutes oftreatment at 85° C. Although the increase in hysteresis after treatmentimplies an energetic change, the mechanisms by which the tissue wasthermally modified are unclear. One possible explanation is provided bystudies examining both the structure of collagenous tissue usingscanning electron microscopy (SEM), and endothermic events, using DSC.Using these techniques, several investigators identified discrete stagesof the denaturation process. They attributed the earliest denaturation(<56° C.) to the destruction of heat-labile cross-links (which are morepronounced in young animals), and showed that the structure of thefibrils remain intact during this process.

A second contributing factor for the biomechanical changes is suggestedby the observed increase in fractional dry mass in both our constrainedand unconstrained treated tissue relative to the control tissue. Theincrease in fractional dry mass indicates that the tissues heated at 85°C. swell less when equilibrated in saline. Since annular tissuehydration has been disclosed to be related to proteoglycan content, ourfinding indicates that the proteoglycans of the annulus have beenaffected by the heat treatment. Similar to collagen, proteoglycans aresusceptible to denaturation through destruction of heat-labile hydrogenbonds. Alteration of annular proteoglycan can affect tissue propertiessince they have been previously disclosed to play a role in stabilizingthe collagen matrix, as had been observed according to at least oneprior disclosure in articular cartilage where the modulus decreasessignificantly when the proteoglycans are removed. It is thus believedthat a portion of the observed biomechanical changes is due to changesin proteoglycan, the thermal properties of which are not extensivelyunderstood according to prior publications. Confirmation of such beliefas to the specific mechanism with respect to proteoglycans may beachieved according to further study and observation by one of ordinaryskill based upon review of this disclosure.

The retarding effect of stress on annular denaturation has a number ofclinically relevant implications. First, to achieve a significant degreeof collagen denaturation in vivo, the annulus should be heated eitherfor long times or at high temperatures, or both. Second, thermaltreatment according to the devices and methods of the present inventionmay be applied in a selective fashion. Since unstressed annular fibersare more susceptible to thermal treatment than stressed fibers, areas ofslack tissue (e.g. the inner annulus in degenerating discs) arepreferentially heated, while preserving structurally competent areasthat are carrying stress (e.g. the outer annulus that retains stressinto later stages of degeneration). Further, patient pre-positioning isdesired for certain circumstances, allowing the practitioner toselectively stress particular annular regions, thereby furthercontrolling the zone of biomechanical alterations.

In another regard, the present invention provides a useful tool whenapplied to selectively shrink proliferative fibrocartilage responsiblefor annular protrusion and prolapse. This is accomplished for example byproviding the thermal therapy to degrade proteoglycans and decreaseswelling.

In still a further regard, and as further supported by the results ofthis study, the present invention is used to provide thermal therapy ina manner specifically adapted to ablate annular nociceptors and cytokineproducing cells while sparing tissue material properties. Thermaltherapy in the range of 48-60° C. is sufficiently low to avoid collagendenaturation and biomechanical changes, yet this temperature region isdesired for modes of thermal spine treatment intended to induce nerveinjury and cellular death without significant biomechanical change fromthe heating (or with biomechanical change if desired and brought aboutby other means).

It is to be further appreciated that the results of this study, as tospecific ranges and/or numbers, are potentially limited by the use ofnon-degenerate porcine intervertebral discs. While porcine discs aresimilar to human discs in many ways, there may be differences indenaturation temperature, which is dependent on a number of factors suchas collagen cross-link type and density. However, the consistent tissuequality and size afforded by the porcine model minimizes inter-specimenvariability and therefore provides a good system by which to investigatemechanisms of thermal/biomechanical interactions. The disc height alsodiffers between human and porcine lumbar discs. Since the lumbar humandisc is generally taller (averaging approximately 11 mm) than theporcine disc (averaging 3 mm in this study), it may be less influencedby vertebral constraint and therefore more able to thermally contract.In this regard, as with many previously disclosed devices and treatmentmethods, the exact extent of effect may vary even between speciesaccording to varied anatomy.

Notwithstanding the foregoing, future studies may be performed on humandiscs according to one of ordinary skill based upon this disclosure toconfirm effects of specific treatment regimens. Moreover, it is furtherbelieved that the relationship between varied temperatures (and/orranges) and predictably varied results are well correlated acrossspecies, though specific temperatures, temperature-time dosing, ormagnitudes of observed results may differ. Accordingly, it is believedthat the studies disclosed herein and aspects of the invention relatedthereto provide beneficial treatment regimens, though such may clearlyrequire further tuning in order to be particularly adapted for specifieduse in treating a particular patient, patient group, or even animaltype.

Further to the experimental model of the present Example, nucleardepressurization allowed for the biomechanical response of the intactannulus to be isolated. However, for intact discs, nuclear pressure willincrease annular stress and therefore is believed to further retardthermal effects beyond that observed here. Finally, the ex vivo studysummarized herein does not characterize any subsequent biologicremodeling that would occur after heat treatment in vivo. Remodelinglikely further modifies annular tissue properties, and the magnitude andtemporal sequence of this response may be further characterized in asuitable in vivo model. However, the acute effects provided hereunderprovide significant benefit notwithstanding such potential forremodeling.

Despite these limitations, the foregoing observations and relateddescription demonstrates a number of mechanisms by which thermal therapyinfluences the biomechanical response of the annulus fibrosus. Uniquefeatures of the disc—specifically tissue structure and stress-strainconstraints due to attachment to adjacent vertebrae—have significantimpact on the thermal treatment effect size. Future in vivo animalstudies and controlled human trials may be further performed by one ofordinary skill in the art based at least in part on this disclosure inorder to further link biomechanical and biological consequences oftissue heating to the various beneficial patient outcomes.

External Directional Ultrasound Thermal Treatment

(“ExDUSTT”) System and Method

The following description relates generally to FIGS. 23-53 and providefurther illustrative embodiments of the invention according to modespreviously described above for providing an external directionalultrasound thermal treatment (or “ExDUSTT”) device, and method fortreating spinal disorders therewith.

As illustrated in FIG. 23, the illustrative ExDUSTT applicator 110 ofthe present invention preferably has a support member 120 with anultrasound transducer 130 mounted thereon within an outer covering 150that is typically an inflatable coupling balloon such as is shown.

According to the further view shown in FIG. 24 during one mode of use intreating a region 108 of an intervertebral disc 104 associated with aspinal joint 101, the transducer is generally chosen to be a curvilinearpanel that is both directional and focusing (e.g. converging signals) tohelp highly localized deep heating, in particular useful forapplications from outside the disc as shown. It is to be appreciatedthat “spinal joint” where used throughout this disclosure generallyincludes intervertebral discs, adjacent vertebral bodies, and associatedstructures such as posterior vertebral elements such as facet joints.

As shown in FIGS. 25 and 26, respectively, ExDUSTT devices of thepresent invention can be on many different delivery platforms, such as arigid pre-shaped platform shown in FIG. 25 with the transducer 130 onthe distal bend section 116 and canted at an angle A for angulardirectional ultrasound relative to the proximal shaft 112 axis, or on acatheter-based platform shown in FIG. 26. Both chassis are beneficialfor respective purposes, and each for common purposes. However, thepre-shaped probe is in particular useful for angular directional heatingat hard to reach places in the body, such as certain spinal locations,and the rigidity helps position control.

FIG. 27A shows an illustrative rigid probe device 200 in finer detailfor further understanding. Distal shaft 202 includes a 4 mm outerdiameter brass tube 204 with 0.008″ silver lead wires 206 and water flowlines (e.g. 0.0226″ polyimide tubing) contained therein and coupled atthe proximal end portion (not shown) to a proximal adapter. A distal0.1135″ stainless steel tubing 208 is shown secured with epoxy 210within the brass tube 204, and has a window 212 cut out leaving supportridges upon which the transducer 230 is mounted with Nusil 1137Silicone, as shown in finer detail in FIG. 27B. Further included beneaththe transducer 230 are rubber threads 236 strung across the window 212to help provide a good non-dampening support system. An outer inflationballoon is shown at 240 and in shadow in the expanded condition fortissue coupling. As can be appreciated from the figure, an air backingis thus provided at 238 to provide highly directional ultrasounddelivery away from the central shaft of the device and out through theeccentric inflation balloon 240 having a diameter D and into tissuethere. Moreover, as illustrated in FIG. 27B, the transducer 230 iscurvilinear having a radius R around an axis that is aligned with thelong axis of the support shaft and thus is focused into tissue along thetransducer and balloon length as such. For the purpose of a completedescription, one exemplary transducer that has been observed to beuseful in this and other ExDUSTT designs herein shown and described hasfor example the following specifications: 0.394″ long×0.98″ wide×0.013″thick PZT4, 0.59″ radius of curvature.

Various modifications may be made to the device just shown anddescribed. For example, the balloon according to that Figure waselastomeric type, such as 0.005″ wall silicone balloon. However, betterrepeatability of size and shape may be required than what suchelastomers can offer, and thus a less compliant balloon of the preformedtype may be used. This is shown for example at balloon 248 in FIGS.28A-B that is for example a pre-shaped PET balloon having a wallthickness for example of 0.001″. Further considerations for materialsmay be considered, such as for example thermal properties, ultrasoundtransmissivity, profile, etc.

Moreover, similar features as just described for the ExDUSTT device maybe incorporated onto a different catheter chassis without much requiredmodification, as referenced in FIGS. 29A-B. Here a proximal cathetershaft 250 is shown coupled to a distal 4 mm OD brass tube 254.Everything else may be the same as described above for the rigid probedesigns. The catheter shaft 250 may be multi lumen, or may be a bundleof lumens, etc.

The transducers shown in the previous FIGS. are not the onlyconfigurations contemplated, either. For example, FIGS. 30A-B show acurvilinear transducer 260 with its radius of curvature R around an axisthat is transverse (e.g. orthogonal) to the long axis L of the supportshaft 280.

Further understanding of various modes of operating devices of the rigidprobe type just shown and described are provided in FIGS. 31A-32B, whichreflect operation at 5.6 MHz optimal frequency, with peak efficiency at40%, and linear output and efficiency out to 12 W applied with 5.5 Wemitted from the transducer.

FIG. 33 shows a test set-up for ex-vivo pig spine treatment using acatheter-based ExDUSTT device over 5 minute heating period, and showscertain measured temperatures during a relatively low temperature modeof operation. T1 is a temperature probe 5 mm deep into tissue from thetransducer coupling interface, whereas T2 temperature probe shows thetemperature profile over varied depths from the transducer.

In contrast to the ex-vivo data shown in FIG. 33, FIGS. 34A-B showresults for in-vivo treatments in pig discs, and show temperatures allexceeding 55 degrees, though temperatures close to the transducerexceeded well over 65 degrees and even up to 80 degrees.

As illustrated in FIG. 35, various different sizes may be used dependingupon the particular need, and a kit of different sizes, lengths, anglesA, radii R, etc. may be provided. The devices 270, 280 shown in FIG. 35generally differ in that the larger device supports a 3.5 mm wideultrasound transducer, whereas the smaller device supports a 2.5 mm widetransducer. In general, other features may be similar unless desired tochange them, whereas for the embodiment kit shown, each device has othercomponents scaled to meet the 2.5:3.5 comparison for the transducerwidths. Other variations may be made, however.

For the purpose of further characterization, and understanding ofdirectivity and focus of energy delivery as relates to the presentinvention, FIGS. 36A-B and 37A-B show certain output power profilesacross the transducer faces for both 2.5 mm and 3.5 mm curvilineartransducers, respectively. The radius of curvature for these transducersis around an axis that is aligned with the long axis of these plots.

Various thermal treatment studies have been performed with workingprototypes of the present invention and will be explained hereafter inpart by reference to the test set-up for the rigid, pre-shaped bentExDUSTT device shown in FIG. 38.

For example, as shown in FIG. 41, all temperatures monitored using 0degree C. cooling during relatively high temperature mode of operationwere above 60 degrees C., even out to 10 mm deep, and in particular wereabove 70 degrees C. for most all data taken at 5 mm depth, whereastemperatures predicted at 7 mm deep were also in excess of 70 degrees.Other illustrative and informative results are reported up through FIG.53 with respect to additional modes of ExDUSTT operation, which are bestunderstood by further reference to the Brief Description of the Drawingsabove.

Various different modes and embodiments for curvilinear transducers maybe suitable for use according to the various embodiments hereindescribed, such as for example the various ExDUSTT device embodimentsjust described However, the following provides some further detail forparticular modes and variations contemplated for the purpose ofproviding a more complete understanding

In one regard, these transducer segments such as used in the ExDUSTTdevices (and per for example the earlier embodiment in FIG. 6C) aresectors of larger diameter cylinders or plated tubes, with ultrasoundenergy emitted from the concave surface. Examples include 0.394″(+/−0.005″)×0.098″ (+/−0.002″) linear wide×0.013 thick which form an14.2 deg. Arc segment of 0.4 “inner radius tube. One can realizedifferent diameters or arc segments, such as 9.5 deg. Arc segment of0.591” inner radius tube. These can be purchased for example fromvendors such as Boston Piezo-optics using materials such as PZT-4, 5, or8.

The radius of curvature can be selected to sharpen or decrease theamount of energy concentration or apparent focusing (i.e., radius ofcurvature of 0.5, 0.75, 1.0, 1.5, 2.0 cm can be appreciated) with thehigher radius of curvature and wider transducers giving more penetratingdistributions. The width can vary to suit particular needs for operationor device compatibility, but may be for example between about 1.5 mm toabout 6 mm; whereas the length can also vary to meet particular needs,such as for example from between about 2 mm to about 10 mm or greater.Transducers meeting these specifications are in particular useful forvarious of the embodiments herein described, provided however that suchembodiments nor other aspects of the invention should not be consideredto be so limited to only these dimensions.

These transducers can be mounted in transducer assemblies using avariety of suitable means. Flexible adhesives (e.g. silicone adhesive,Nusil), rigid epoxies or conformal coatings (Dow Corning) may be used.Rigid metal (brass or stainless steel) or plastic assemblies can bemachined to hold the transducers and maintain air-backing. One moredetailed example incorporated into many of the ExDUSTT devices shown anddescribed includes a filed down, 15 mm long portion (or specifiedlength) across a 180 degree plane transversely through a distalstainless-steel support hypotube. This forms a shelf for either side ofthe transducers to be mounted. Lead wires (such as for example eithersilver lead wire or miniature coaxial cable (Temflex, Inc)) are solderedto the transducer surfaces for power application and can be run withinthe central lumen of the SS.

A thin layer of silicone adhesive can be placed upon the edges of thetube structure, and the transducer segment placed. The transducer canthen be sealed using silicone adhesive and/or conformal coating. Theconformal coating can be accelerated using elevated heat for about 60min. Alternatively, rubber thread can be used for a spacer with siliconeadhesive, to keep transducers from contacting the metal surface. Otherholding devices can be implemented, including pieces machined from brassbar or rod with gaps for the air space and offsets to support. In someimplementations, it may be desired to circulate water or fluid behindthe surface of the transducers.

These transducer assemblies can be either modular catheter forminsertion into target tissue (intra-discal) or rigid externalapplicator. It is not necessary, but these transducers can be sealedusing epoxy and polyester layers a previously described, or usingmineral oil or other type of oil instead of Epotek, or the transducercan be left bare, though in many applications would be sealed on itsedges and possibly top surface with conformal coating for watertightintegrity and durability. Custom multilumen extrusions in materials suchas pebax can form the flexible catheter member of which the transducerassembly is attached. The transducers are rigid, but if multiplesegments are used, they may be coupled in a manner providing flexiblehinges for better bendability in use.

Pre-shaped high-pressure balloons such as those herein shown forultrasound tissue coupling can be provided in various shapes. Suitablesources include for example custom fabrication, such as for example byAdvanced Polymers, or may be made in house by heat-stabilizing the PETheat-shrink in pre-determined shape using molds and Teflon-coatedmandrels. These balloons can have a neck that is 3 mm OD and a one sidedinflation with a 2 mm radius. Compliant balloons using silicone, c-flex,polyurethane, or other material can also be used for variousapplications indicating such compliance or elastomeric properties.

These devices can have temperature regulated flow, flow in general, orno flow at all. In addition, devices without encapsulating balloons canbe realized with sterile saline or fluid flow used to cool and couple USto the interface.

Internal Directed Ultrasound Thermal Therapy (“InDUSTT™”) System andMethod

The following description relates to device and method embodiments inparticular adapted for use internally within intervertebral discs orother joints, e.g. “InDUSTT” devices and methods.

The following figures and accompanying description is to be read inconjunction with prior description herein made above, and in any eventrelate to InDUSTT devices such as that shown at catheter 290 in FIG. 54.More specifically, FIG. 54 illustrates arrangements for two alternativemodes of InDUSTT assemblies and treatments as follows. Catheter 290 isshown at the top of the Figure in a “direct coupling mode” and isadapted to be delivered directly into a region of a spinal joint, e.g.within the disc or bony structure, with the transducer coupled directlyto tissue. Thus, there is only shown a coupling 294 such as forelectrical leads 296, and fluid cooling coupling 298. As shown in theassembly of FIG. 54 on the bottom, however, a catheter cooled or “cc”arrangement differs from the direction coupling or “cc” arrangement inthat a catheter 290 is buried within a closed housing of an outerdelivery device 300 that has a sharp pointed tip 302 for puncturing intoan intervertebral disc. Water circulation ports 298,310 according tothis arrangement cycle cooling fluids between a lumen within theinternal catheter 290 and over the internal catheter 290 but within theouter sheath 300.

Further details of the cc arrangement are variously shown in FIGS.55A-C, wherein a transducer 320 is of a cylindrical tubular type thathas sectored grooves 322 (FIG. 55C) on either side of an electroded andactive portion 326 for directional ultrasound delivery along about a 90degree span of space radially outward from that section, and thus bothdirectionality is achieved, as well as diverging US signal. Couplersshown include power lead coupler 294, water inflow coupler 298, wateroutflow coupler 310. As shown in FIG. 55B, the water cooling is aided bya distal port 299 in the internal catheter device 290. A thermocouple330 is shown along the active sector, as well as others may be providedelsewhere (not shown) such as along the other dead sector as temperaturemonitoring may still be important there to protect certain tissues fromconductive heating during US therapy on the opposite side of thecatheter. The transducer shown may be for example 1.5 mm outer diameter,0.9 mm inner diameter, by 10 mm long and mounted over a plastic supportring. The outer catheter 300 may be for example constructed from asimple polymeric tubing such as made from CELCON™ from Best Industriestypically used conventionally for implanting radiation seeds in tumortherapy and of 13 gauge construction.

For the purpose of providing a thorough understanding of the manydifferent aspects and considerations of using the InDUSTT device justdescribed, a significant amount of summary results from multiple studiesof working embodiments is herein provided by reference to FIG. 56A andbeyond. A thorough understanding of various aspects of these results andexperimental arrangements shown is gleaned by review of the BriefDescription of the Drawings above. In general, where discs are indicatedby an arrangement such as “C3-4” or “C4/5” such designates the vertebraein the animal between which the disc was treated. In addition, curvelegends designating numbers for graphs (such as for example “Probe 1-1”,“Probe 1-2”, etc. in FIG. 65A) designate thermocouples along temperaturemonitoring probes in the disc tissue, typically spaced by 5 mm apart.

Accordingly, as is reflected in the graphs and other pictures andFigures, many different discs were treated. Still further, the testresults shown also reflect an understanding of the effects of cooling atdifferent temperatures, as well as direct coupling versus cathetercooled coupling, as well as relatively high versus relatively lowtemperature modes of use.

While the results shown in these latter FIGS are in non-human animalmodels, the results, and in particular the relationships between resultsbetween different treatment groups, correlate to the human condition andare confirmed by earlier human cadaver studies performed. Actual valuesmay of course differ, however, but it is believed that the extreme endsof the results would apply across vertebrate animal species. Moreover,the date suggests that directivity is confirmed, as is the ability toachieve high temperatures over 70 degrees or even 75 degrees, as well ascontrol heating to lower temperatures for other intended treatments.

In one example, FIGS. 59A and B show two sets of lines that cross attime equal to about 900 seconds. This indicates a period of time whenthe InDUSTT device, with sectored, directional ultrasound emission, wasrotated. Accordingly, the uniform change in temperature reflects thepreferential heating that can be achieved with such device and notheretofore possible. For further illustration, FIG. 65A shows similarresults according also to turning a directional device to realign theactive sector to different transducers.

Various embodiments have been herein described, including ExDUSTT,InDUSTT, rigid-probe based, catheter based, directly coupled, activelycooled, sectored transducers, curvilinear transducers, axially alignedtransducers, transversely aligned transducers, relatively largetransducers, relatively small transducers, compliant elastomericcoupling balloons, relatively non-compliant pre-formed couplingballoons, relatively high temperature modes of operation, relatively lowtemperature modes of operation, low temperature cooling, roomtemperature cooling, preshaped, flexible, guidewire delivery, anddeflectable/steerable delivery platforms. It is to be appreciated thatthe more detailed description for such embodiments provided herein isfor the purpose of illustration, and other modes of achieving such maybe suitable for inclusion according to the invention without departingfrom the present scope. Moreover, the combinations of such featuresherein shown are highly beneficial, but not intended to be limiting.Other combinations may be made without departing from the intended scopehereof. For example, the particular embodiments shown and described for“ExDUSTT” applications are described as such merely according to theirhighly beneficial ability to perform in that arrangement, but they maybe used as InDUSTT devices as well, despite their particular externaluse benefits. The opposite is true, as well, with respect to InDUSTTdevices which may also be used in other external locations such as fordisc heating. The devices shown and described may be used within oraround the bony structures of spinal joints, too. Moreover, wherevarious of the features may be highly beneficial for particularapplications, they may not be necessary for other applications. Forexample, directional energy delivery is a highly beneficial aspect ofthe various ultrasound embodiments herein shown and described, inparticular where highly localized heating is desired while othersurrounding tissues need to be protected such as nerves. However, inother applications, such as some complete disc remodeling applicationsfor example, non-directional emission may be suitable to heat all thesurrounding tissue equally.

It is to be appreciated that the various modes of devices and operationherein described, together with tissue characterization studiesperformed and herein presented, provide a significant understanding withrespect to adapting and controlling thermal therapy, or other modes ofultrasound delivery for therapy, in special areas in the body such asjoints, and in particular spinal joints and their discs and bonystructures. Back pain and other issues in these joints are significantmedical issues that may be addressed with the present inventionaccording to its many different modes and aspects.

Long-Term Implantable Ultrasound Delivery Devices, Systems, and Methods

The foregoing embodiments, including the devices, systems, and methodsdescribed, have been generally described above with respect to their useas temporary implants, (e.g. per the percutaneous catheter or probedevices and respective treatment techniques described in the precedingFigures, such as for example with respect to the various ExDUSTT andInDUSTT devices shown and described). However, according to a highlybeneficial aspect of the present invention, an ultrasound treatmentsystem and method is provided for long-term implantation, eitherpermanent or semi-permanent, as is described in more detail below byreference to various embodiments.

The long-term implantable ultrasound system of the invention is shownschematically according to various illustrative embodiments in FIGS.66-68 by reference to a patient's body 402 that includes a spine 404 andouter skin barrier 408.

More specifically, FIG. 66 shows long-term implantable ultrasoundtherapy system 400 and includes a long-term implantable ultrasoundtreatment assembly 420 positioned at a location adjacent to a spinaljoint 406. A coupling assembly 430 connects treatment assembly 420 witha control unit 440 that is shown in this embodiment to also be implantedas a long-term implant within the body 402 of the patient. Control unit440 includes for example a power source 442 that cooperates with acontroller 444. Further to the illustrative embodiment, control unit 440is adapted to communicate with an external assembly 460 via atransmitter 448 and a receiver 450 of control unit 440 and reciprocaltransmitter 468 and receiver 470 for external assembly 460. Suchcooperation may be for example in order to provide telemetry to receiveand process data monitored by control unit 440 regarding the treatmentwith ultrasound assembly 420, such as monitored parameters including forexample temperature, thermal dose, number of treatments, duration oftreatment, power levels. Or, such cooperation between internallyimplanted control unit 440 and external assembly 460 may be for thepurpose of downloading new software such as operation protocols to thedrive unit 462 tailored to advance therapy to account for newtherapeutic information or to advance or otherwise modify an overalltherapy protocol to a different stage. Or, to the extent power source442 is a rechargeable battery, coupling between control unit 440 andexternal source 460 may be done for the purpose of recharging thebattery, which may be done across the patient's skin barrier 408according to previously disclosed methods, though which may be modifiedto meet the particular needs for a particular case. Examples of suchremote, transdermal power recharging include use of induction bycreating a magnetic field across the skin barrier 408 in a particularmanner so as to recharge the batter of power source 442.

FIG. 67 shows another embodiment similar to that of FIG. 66, excepthowever that control unit 440 is positioned externally of body 402 suchthat coupling assembly 430 bridges across the skin barrier 408. Thisprovides the ability to recharge, monitor, control the control unit 440and related treatment without requiring the remote transmission acrossthe skin barrier 408 and other tissues as required in the FIG. 66embodiment. According to this and the FIG. 68 embodiment, the externallylocated control unit 440 has a coupler 446 that is adapted to couple toexternal assembly 460 via its reciprocal coupler 466, which is shownschematically but may be for example for similar communication purposesprovided above with respect to sending and receiving data and otherinformation to monitor or control therapy.

In addition, such couplers 446,466 may provide for a recharging of thepower source 442, such as a rechargeable battery. In still anotherregard, control unit 440 may be replaced by a simple coupler for thevarious leads connecting ultrasound assembly 420 with the outside world,and all control of therapy is done via a removable attachment to theexternal assembly 460. This may in particular be useful with respect totherapy protocols requiring relatively few, discrete applications ofenergy that will thus allow for selective attachment to the therapeuticcontrol system.

FIG. 68 shows yet another embodiment similar to FIG. 67, except howeverillustrating that the ultrasound treatment assembly 420 is positionedwithin a structure of the spinal joint 420, which may be for example abony structure such as vertebral body or posterior body, e.g. facetjoint, or may be an intervertebral disc.

It is to be further appreciated that these embodiments, and inparticular the embodiments of FIGS. 67 and 68 providing external accessto control unit 440, may beneficially provide features not easilyprovided in the completely implanted embodiment of FIG. 66. For example,cooling assemblies may be incorporated into the externally accessibleembodiments, such as circulating cooling fluids to a cannula portprovided there. However, it is further contemplated that cooling may beaccomplished with the fully implanted assembly, such as by circulatingcooling Freon within a closed internal loop between control unit 440 andtransducer assembly 420, or merely circulating water at body temperaturetherebetween, though such may be gradually elevated during the thermaltherapy, but nevertheless provides a heat sink to circulate heatconduction away from the treatment area.

Accordingly, the various embodiments previously described above withrespect to ExDUSTT and InDUSTT ultrasound delivery system arrangementsmay be appropriately adapted for use with the long-term implantarrangement of the present invention to provide long-term thermaltherapy with various beneficial aspects of those prior devices. Suchmodifications may be made, for example, to materials of contruction,shapes, size, etc., to adapt them for particular intended long-term use.Moreover, various disclosures cited above with respect to long-termelectrical implants may be further modified to accommodate theparticular needs to delivery, drive, operate, and monitor ultrasoundtherapy according to the present invention. In addition, variousfeatures provided with respect to other ultrasound energy deliverysystems disclosed among various published references may also beappropriately modified with respect to the long-term, implantableultrasound therapy provided herein.

It is to be appreciated therefore that the present invention satisfiesthe foregoing needs left heretofore unmet by prior disclosures byimplanting, in one regard, an ultrasound therapy source in the patientand providing for the heat source to be controlled automatically ormanually. This allows for automatic, periodic treatment and/or manualcontrol by a patient or health care professional.

By way of example, and not of limitation, in addition to the variousembodiments provided herein above by reference to the various Figures, aheat source such as that described in U.S. Pat. No. 5,620,497 (butminiaturized if desired) would be implanted in a target site. The targetsite could be soft tissue, a joint, the spine, or any other location inthe body where application of heat will yield a desired effect. Coupledto the heat source is a control apparatus, such as a microprocessor,that will activate the heat source at predetermined times toautomatically provide for periodic treatment. Using conventionalprogramming techniques, the microprocessor can administer a treatmentcontinuously or at spaced apart intervals. Application of heat during aparticular treatment interval can be with continuous wave heat or pulsedapplication of heat. Combinations of continuous wave and pulsedapplication of heat can be programmed as well. The treatment could berepeated after a predetermined time period, such as once every hour,once every day, or any other desired period of time. Another example ofa treatment would be to heat a target region for a fixed duration onceevery week for two months. Such controls would be contained for examplein the control module 440, or external assembly 460, or a combination ofresources allocated between them, such as shown for example in any ofFIGS. 66-68.

It is to be further appreciated by reference to the illustrativeembodiments of FIGS. 66-68 that control of the applicator should beconsidered broadly, though particular benefits are gained by each of theparticular embodiments between those figures such that the applicator(heat source) can be activated/controlled via telemetry, an isolatedself-contained implantable control unit, or via percutaneous orextracorporeal connection (such as catheter(s)) to exterior control andmonitoring device(s).

In one further mode, a manual control can be provided so that thepatient can “force” a treatment in response to pain or another sensorystimulus. The software will “intercept” the manual control signal andcompare the time between the manual control signal and the priorautomatic treatment, or between two prior manually forced treatments, todetermine if the interval between treatments is too short. If so, themanual control would be locked out until at least a predeterminedinterval has passed. Optionally, the passing of the interval can besignaled to the patient using visual and/or audible indicators such aslights and buzzers. Or, more control can be left to the patient withoutsuch preventative measures required.

The control apparatus portion of the invention can be external to thepatient, such as worn in pouch on a belt or in any other convenientmanner. Such applies for example to either or both of external assembly460 (if included) and control unit 440 (e.g. per the FIG. 67-68embodiments). Leads from the ultrasound transmission source would, inthat case, extend through the patient as is known with otherelectrically operated implantable devices such as for example certaininsulin pumps or temporary cardiac pacemakers or defibrillators. Thepatient then could wear the apparatus, and an associated battery powersupply, on his or her body.

In another embodiment, the entire apparatus, including power supply,could be implanted, again using techniques and arrangements known forother systems and methods, such as in the cardiac pacemaker art,electrical spinal stimulator systems, and the like. Another exampleincludes an implantable ultrasound heating apparatus adjacent tointervertebral disc for chronic treatment of lower back pain. The devicecould deliver a single treatment session on demand (pain) of thepatient, or follow some protocol.

According to further embodiments, temperature sensors could be used fortreatment control and verification-feedback. A heating or acousticdevice can be inserted into a tumor for repeated heating and activationof chemotherapeutic agents on a semi-regular basis. A drug can bereleased from the applicator, such as via a reservoir or elutingcoating, or another implant closely associated therewith.

It is further contemplated that the devices of the present inventionbeneficially use ultrasound delivery according to highly beneficialembodiments. Such delivery may be for heating, such as described indetail above by reference to the prior embodiments. Or, such ultrasounddelivery may be for other purposes in addition to or alternative toheating, as will be explained further below. Moreover, other sources maybe used in conjunction with or instead of ultrasound. Radio-frequencycurrent, microwave, thermal conduction based sources, magnetic, andlaser sources can each be utilized.

Additional examples of various modes of use include, but are not limitedto: frequent ultrasound exposure to bony endplates to stimulate bonegrowth; intervertebral fusion; and ultrasound exposure ofpostero-lateral processes for fusion.

Accordingly, the invention provides a long-term, permanent orsemi-permanent implant, and thus modifies the non-permanent devicesheretofore used for ultrasound thermal therapy. The heat source wouldemploy biocompatible, flexible technology that can be permanently orsemi-permanently implanted to maintain the desired treatment (whetheracoustic exposure or thermal) protocol. Moreover, it is alsocontemplated that, despite the benefits provided for such long-termadaptive use, the present embodiments may also be used as temporaryimplants, such as in certain more acute settings under the care ofhealthcare professionals.

The wire leads for thermometry sensing and power leads are connectedthrough skin/body wall and sutured in place. Cooling tubes may befurther provided if cooling is necessary or desired. For example, suchcooling arrangements as described above for the previous embodiments maybe further adapted for use in the long-term implant systems of thepresent embodiments, including with respect to particular temperatures,such as for example at: less than 37 degrees C. (such as 0 degrees C.);over 37 degrees C.; and in some cases 43 degrees C. or above. Moreover,the various modes for fluid flow in and around the transducer may beused, and cooling may be provided for tissue interface regions, or fornon-targeted tissues.

Further contemplated for use within system 400 according to the variedembodiments among FIGS. 66-68 may be temperature regulation, such as byuse of thermal sensors (e.g. thermocouples or thermisters) located in oraround the transducer assembly. Such aspects may be according to thevarious embodiments incorporating temperature monitoring and control aselsewhere herein described for the various embodiments above.

Tissue coupling may also be achieved according the various embodimentselsewhere herein described for temporary implants, though may be againmodified to suit the particular needs for long-term implantation, suchas with respect to minimizing the intrusiveness by providing reduceddimensions (e.g. with respect to coupling pads or balloons), ormodifying the types of materials used. For example, for highly compliantballoon materials, long term inflation may result in significant creepand expansion of the membrane that may produce undesired results, andthus for certain such long-term implants balloons of the less compliantconstruction may be desired with respect to that consideration. However,the balloon materials may also be chosen to minimize potential long-termwear and tissue erosion issues that might arise at the tissue interface.This may be particularly important for implants at locations wheremotion is experienced, such as at mobile portions of spinal joints. Insuch case, more compliant balloon materials may be less traumatic overprolonged periods of time with movement experienced at such interface.

It is contemplated that the overall cooperation between components insystem 400 shown in FIGS. 66-68 may be accomplished according to a widevariety of arrangements, and thus the coupling assembly 430 is shownvery schematically. Such assembly 430 may include for example a singlecannula connecting transducer assembly 420 and control unit 440, whichcannula may house transducer power delivery leads, fluid delivery lumensfor coupling balloon inflation and/or cooling fluid circulation,temperature sensor leads, or the like. These may share lumens in variouscombinations, or a multi-lumen assembly may be provided. Or, separatemembers may be used to connect such coupling elements between controlunit 440 and ultrasound transducer 420. In this arrangement, though moreattaching members are strung within the body, they may be renderedsmaller and more flexible, and their overall effect may be lessintrusive to the body's internal environment than would result from asingle or even multiple combination bundle(s), respectively.

The various modes of operation for the ultrasound implants generallyrequire use of an RF Oscillator, such as for example operating betweenabout 0.5 to about 12 MHz, and with pulse modulation for various of themodes described above, or without such modulation for continuous waveembodiments. Moreover, an RF power amplifier may be incorporatedtherewith. Such may be provided in the control unit 440 directly coupledto the ultrasound transducer 420 and worn as the internal or externalimplant in or on the patients body, respectively, per the embodimentsshown in FIGS. 66-68. Or, coupling to a remote external source withthese features may be used, such as at external assembly 460 in thoseFigures. This may be in particular the case for example when therapeuticultrasound delivery is desired only at discrete periods of time and thepatient may hook-up to the RF drive assembly that drives the transducer.

Accordingly, RF sources previously described with respect to ultrasoundtherapy systems, or those previously disclosed for use with respect toelectrical energy delivery implants, may be modified appropriately tomeet the unique needs for driving the long-term implantable ultrasoundtransducers of the invention and according to the therapeutic rangesdesired, such as those illustrative modes of operation herein describedabove.

Various modes of ultrasound delivery are contemplated, either to providethermal therapy, or non-thermal ultrasound therapy, and whether toprovide for mechanical tissue remodeling, controlled cell death, orenhanced tissue permeability to drug delivery. In one regard, withrespect to desired levels of thermal therapy using the ultrasoundsystems, such modes of therapy previously described above with respectto the other embodiments described by example for temporary implant usemay be accomplished with the implantable systems of the presentembodiments.

Various particular modes of operation and intended therapies areadditionally provided as follows for further illustration.

According to one exemplary mode, ultrasound is delivered with a powerbetween about 0.1 to about 1 W/cm2, operated at about 1.5 MHz, and at 1kHz repetition with 100-200 micro-second burst (100-200 cycle burst) forexample a total of between about 10 to 30 minutes daily. This isconsidered beneficial for example for stimulating bone growth.

According to another mode for more elevated heating, ultrasound isdelivered with a transducer emission power between about 0.5 to about 2W/cm2, at frequencies between about 5 to about 12 MHz, according tocontinuous wave delivery modes. Such may be continual all the time,though power limitations may require significant interface with externalpower sources, and tissue tolerance and/or degradation may result. Or,such may be limited in total time over a given period, such as forexample between about 5 to about 60 minutes/day. This is useful forexample to achieve moderate heating considered to be beneficial forexample to provide enhanced drug delivery therapy.

Where long-term, continual drug delivery enhancement is desired, aprotocol of timed bursts may also be used as follows. Power may bebetween about 1 to about 30 W/cm2, with bursts lasting between 50 to 200microseconds, repetition between about 1 Hz to about 5 kHz, and withultrasound frequencies between about 0.5 to about 15 MHz.

In still another mode, delivery of up to about 12 to about 15 MHz isconsidered beneficial for providing both heating in addition to acousticstimulation.

Various time periods may be employed for ultrasound delivery, includingfor example periods of energy delivery of 5, 15, 30, 60, 120, or moreminutes, which can be given multiple times per day, for extended timeperiods. These periods may represent continuous wave, pulsed burst wave,and may be in one treatment segment, or aggregated over various spacedtreatment intervals.

The parameters provided above for various different heating modalitiesare illustrative only, and may be varied according to a particularcombination of conditions and other related parameters for operation, aselsewhere herein described. For example, where power output is describedby way of W/cm2, other parameters may be observed and/or controlled fordesired results, such as for example power per length of transducertreatment segment, e.g. 0.1-10 W per 1 cm applicator length. In anotherexample, where particular frequency ranges are desired, this may allowparticular transducer constructions to be used for optimal overallresults, such as adjusting the size to meet the frequency of operation.For example, lower frequency transmissions are generally accomplished bytransducers of larger wall thickness than higher frequencytransmissions.

Therefore, various ultrasound transducers are considered useful for thepresent long-term implant embodiments and may be similar to otherspreviously described above, though in many cases will be modified tosuit the different long-term implant needs, either by physicalconstraints, or according to different desired modes of operation.Examples of transducers considered suitable for many indicationsinclude, for example, providing the transducers according toconstructions that are adapted to operate between about 0.5 and about1.5 MHz., which would be useful for pulsing at low frequencies. Furtherdetails of a suitable transducer may include for example a PZT4 material(or 5 or 8) with wall thickness for example of about 0.058 “for 1.5 MHzvariety and about 0.174” for 0.5 MHz varieties. Examples of appropriatelead wire assemblies include lead wires of about 0.002″ thickness foruse with low energy ultrasound applications.

Various materials for construction may be used to make the long termimplantable parts of the overall implant system, such as leadassemblies, e.g. coupling assembly 430 in FIGS. 66-68, or with respectto housing the transducer(s). Examples of suitable materials may includesilicone (Nusil™, e.g. Nusil™ 6640), Pebax™, and polyester (e.g.commercially available from Advanced Polymers) to the extent compatiblewith long term implantation. Moreover, coatings may be used on suchmaterials to enhance biocompatibility, including bioactive agents suchas anti-inflammatory, healing promoters, or other species of agents maybe used to meet the particular needs. Moreover, such agent coatings maybe adapted to elute from the implantable device surface to providetreatment to the tissue interfaced with or around the device, eitherwithin the zone of ultrasound treatment, or outside the targeted range(e.g. for protective therapy in view of the thermal conduction in thearea, such as to enhance protection of nerves).

Suture tags or other mechanisms such as fixation loops may be placedalong edges of applicators or transducer assembly for permanentattachment or semi-permanent fixation of device. Many such fixationdevices have been previously disclosed, and may be modified for useaccording to the present invention by one of ordinary skill based uponreview of this disclosure. In any event, the configuration and type ofsuch fixation device may be particularly tailored for the intendedenvironment where the transducer assembly is to be positioned forlong-term implantation. Such may affix to bone, connective tissue, ormuscle in the adjacent tissue. Moreover, fixation may also beimplemented for the control module and/or power source if also implantedwithin the body, as well as the respective coupling assembly orassemblies between the ultrasound treatment assembly and the respectivecontrol unit.

Pulsed ultrasound delivery is one particular mode for operating theimplantable ultrasound delivery device of the present invention. In oneparticular regard, such mode of operation is considered highlybeneficial for regeneration of various tissues. For example, therapeuticangiogenesis is the controlled induction or stimulation of new bloodvessel formation to reduce unfavorable tissue effects caused by localhypoxia and to enhance tissue repair. The effects of ultrasound on woundhealing, chronic ulcers, fracture healing and osteoradionecrosis may beexplained by the enhancement of angiogenesis. Optimum intensities ofbetween about 0.1 and about 0.4 W/cm2 (e.g. special average temporalaverage or “SATA”) with 1 MHz ultrasound stimulates the production ofangiogenic factors such as IL-8, fibroblast growth factor (bFGF) andvascular endothelial growth factor (VEGF) in cells such as osteoblastsand fibroblasts. Such is in particular applicable to long-term implantssuch as according to the present invention, though it is contemplatedthat repeat treatments with temporary implants may accomplish suchresults, such as according to the prior embodiments above. However, suchrepeated temporary modes of therapy would also require increasedmorbidity associated with repeat invasions into the body.

The following are further illustrative examples of modes of operationintended to provide certain desired results.

In one regard, a pulsed ultrasound delivery modality (e.g. less than orequal to about 70 microseconds) at about 5 MHz frequency of oscillationis considered applicable for uses where nerve stimulation is desired.

Low-intensity US accelerates regeneration of peripheral nerves,repairing of pseudarthrosis and bone fractures, will enhance formationof new bone tissue, osteogenesis and in the repairing of fractures.

Ultrasonic treatments at 0.5 W/cm2, 1.5 MHz, for durations of 5, 15, and25 min/day for four weeks, will accelerate bone formation at thefracture site for such durations. Ultrasound at 0.5 W/cm² arestimulatory to fracture repair, if given for example for about 15min/day.

Ultrasound at an intensity equal to about 0.4 W/cm², and at frequency ofabout 1 MHz, will stimulate collagen synthesis in tendon fibroblasts inresponse to an injury of the connective tissue matrix, and alsostimulate cell division during periods of rapid cell proliferation.Increasing the treatment time, such as for example doubling thetreatment time to 40 minutes daily, will significantly increase thehistologic quality of repair cartilage. Daily low-intensity pulsedultrasound will have a positive effect on the healing of osteochondraldefects, with 40 minutes daily significantly increasing the histologicquality of the repair cartilage.

Further more detailed information related to various modes of thermaltherapy and/or ultrasound delivery and related effects on tissue, andwhich provide further understanding of the various operational modesjust described above according to using long-term implantable devicesaccording to the present invention, is generally disclosed among thefollowing references: Cook, J. L., J. L. Tomlinson, et al. (1999).“Induction of meniscal regeneration in dogs using a novel biomaterial.”Am J Sports Med 27(5): 658-65; Cook, S. D., S. L. Salkeld, et al.(2001). “Improved cartilage repair after treatment with low-intensitypulsed ultrasound.” Clin Orthop (391 Suppl): S231-43; Ramirez, A., J. A.Schwane, et al. (1997). “The effect of ultrasound on collagen synthesisand fibroblast proliferation in vitro.” Med Sci Sports Exerc 29(3):326-32; Reher, P., N. Doan, et al. (1999). “Effect of ultrasound on theproduction of IL-8, basic FGF and VEGF.” Cytokine 11(6): 416-23; Rubin,C., M. Bolander, et al. (2001). “The use of low-intensity ultrasound toaccelerate the healing of fractures.” J Bone Joint Surg Am 83-A(2):259-70; and Tsai, C. L., W. H. Chang, et al. (1992). “Preliminarystudies of duration and intensity of ultrasonic treatments on fracturerepair.” Chin J Physiol 35(1): 21-6; Foster K R, Widerhold M L,“Auditory responses in cats produced by pulsed ultrasound,” J Acoust SocAm. 1978 April, 63(4):1199-205. The disclosures of these references areherein incorporated in their entirety by reference thereto.

Additional information related to various aspects generally ofimplantation in and around the spine, various additional modes ofoperating implantable energy delivery devices, or various differenttypes of conditions that may be also treated according to the presentinvention may be found in one or more of the following issued U.S. Pat.No. 6,233,488 to Hess; U.S. Pat. No. 6,493,592 to Leonard et al. Stillfurther information is provided in one or more of the following U.S.Patent Application Publications: 2001/0049527 to Cragg, now U.S. Pat.No. 6,558,390; and 2002/0115945 to Herman et al., now U.S. Pat. No.7,065,408. More information is also provided in the following PCTInternational Publication: WO 02/09808. Whereas the various disclosuresof these references do not describe a long-term, implantable therapeuticultrasound system such as according to the present invention, theirdisclosures may be considered helpful in gaining a completeunderstanding of certain aspects of the invention and various intendedenvironments of use, and therefore are herein incorporated in theirentirety by reference thereto.

Other modes of using the long-term implantable ultrasound therapydevices of the invention are also contemplated, including in combinationwith other therapies for cooperative effects. For example, theultrasound therapy may be used for or during local anesthesia. Examplesof disclosures intended to provide prolonged local anesthesia, such aswith respect to joints and other body spaces, are variously provided inthe following issued U.S. Pat. No. 6,046,187 to Berde et al.; U.S. Pat.No. 6,248,345 to Goldenheim et al.; and U.S. Pat. No. 6,426,339 to Berdeet al. The disclosures of these references are herein incorporated intheir entirety by reference thereto.

Again, many different modes of operation, and intended therapeuticeffects, have been provided to give a thorough understanding ofapplications by which the long-term implantable ultrasound therapysystems of the invention provide clinical benefit. However, other modes,specific designs and constructions, may be specially adapted forparticular applications and according to particular constraints, such asfor example patient anatomy, time of treatment, extent and area oftissue to treat, frequency of pain, etc. Such modifications areconsidered within the intended scope of the present invention, whichshould be considered broadly.

Moreover, ultrasound has been featured as the highly beneficialtherapeutic energy source of choice for the various embodiments hereinshown and described. However, other energy sources should be consideredwithin the intended scope of various aspects of the invention to theextent capable of achieving such desired, novel results. Examples ofsuch aspects include: active cooling (including at the transducer,interfacing tissue, or non-targeted tissue); directional energycoupling; focused energy delivery (e.g. converging energy signals); useof coupling members to achieve uniform energy delivery into tissueinterface; thermal treatments according to specified thermal dosing ortemperature ranges to achieve certain desired tissue responses; andcoupling of energy into tissues with desired temperature elevations atvarious depths of tissues (and within desired ranges of time).

Although the description above contains many specificities, these shouldnot be construed as limiting the scope of the invention but as merelyproviding illustrations of some of the presently preferred embodimentsof this invention. Thus the scope of this invention should be determinedby the appended claims and their legal equivalents. Therefore, it willbe appreciated that the scope of the present invention fully encompassesother embodiments which may become obvious to those skilled in the art,and that the scope of the present invention is accordingly to be limitedby nothing other than the appended claims, in which reference to anelement in the singular is not intended to mean “one and only one”unless explicitly so stated, but rather “one or more.” All structural,chemical, and functional equivalents to the elements of theabove-described preferred embodiment that are known to those of ordinaryskill in the art are expressly incorporated herein by reference and areintended to be encompassed by the present claims. Moreover, it is notnecessary for a device or method to address each and every problemsought to be solved by the present invention, for it to be encompassedby the present claims. Furthermore, no element, component, or methodstep in the present disclosure is intended to be dedicated to the publicregardless of whether the element, component, or method step isexplicitly recited in the claims. No claim element herein is to beconstrued under the provisions of 35 U.S.C. 112, sixth paragraph, unlessthe element is expressly recited using the phrase “means for.”

What is claimed is:
 1. A method for delivering ultrasonic energy withina vertebral body of a vertebra to treat skeletal joint pain of asubject, the vertebral body comprising a bony structure located above alower vertebral endplate and below an upper vertebral endplate of thevertebra, the method comprising: penetrating a vertebral body byinserting a distal end of a cannula through an outer wall of thevertebral body and within the bony structure of the vertebral body;wherein the cannula comprises a sharp distal tip and a central bore;inserting an ultrasound energy delivery device through the central boreof the cannula and into the vertebral body; wherein the ultrasoundenergy delivery device comprises at least one ultrasound transducer; andactivating the ultrasound energy delivery device to deliver ultrasoundenergy to at least a portion of the vertebral body sufficient todenervate a target region of the vertebral body; wherein the ultrasoundenergy delivery device is positioned within the vertebral body when theultrasound device is activated.
 2. The method of claim 1, whereininserting the ultrasound energy delivery device through the central boreof the cannula and into the vertebral body comprises advancing theultrasound energy delivery device out of the distal tip of the cannula.3. The method of claim 2, wherein the ultrasound energy delivery deviceis configured to deliver ultrasound energy in a first direction, andwherein the ultrasound energy delivery device is configured not todeliver a substantial level of ultrasound energy in a second direction.4. The method of claim 1, further comprising deflecting a deflectableportion of the ultrasound energy delivery device.
 5. The method of claim4, wherein the ultrasound energy is delivered from the deflectableportion of the ultrasound energy delivery device.
 6. The method of claim1, further comprising steering the ultrasound energy delivery device tothe target region.
 7. The method of claim 6, wherein the ultrasoundenergy delivery device is steered by manipulating a proximal end of theultrasound device.
 8. The method of claim 1, further comprising passingcoolant through a portion of the ultrasound energy delivery device tocool at least one of the portion of the vertebral body and the at leastone ultrasound transducer.
 9. The method of claim 1, further comprising:removing the ultrasound energy delivery device from the body of thesubject; and removing the cannula from the body of the subject.
 10. Themethod of claim 1, wherein the ultrasound energy delivery device isdelivered as a long-term implant.
 11. The method of claim 10, whereinthe long-term implant comprises a control unit, a receiver, and atransmitter configured to facilitate communication with an externalsource outside of the body of the subject.
 12. The method of claim 1,wherein the ultrasound transducer delivers a converging field ofultrasound energy to the region of tissue.
 13. The method of claim 1,wherein the ultrasound transducer delivers a diverging field ofultrasound energy to the region of tissue.
 14. The method of claim 1,wherein the ultrasound transducer delivers a substantially collimatedfield of ultrasound energy to the region of tissue.
 15. A method fordelivering ultrasonic energy within a vertebral body of a vertebra totreat skeletal joint pain of a subject, the vertebral body comprising abony structure located above a lower vertebral endplate and below anupper vertebral endplate of the vertebra, the method comprising:inserting a distal end of a spinal needle through an outer wall of avertebral body and within the bony structure of the vertebral body;wherein the spinal needle comprises a sharp distal tip configured topenetrate the outer wall of the vertebral body and a needle bore;inserting an ultrasound energy delivery device through the needle boreof the spinal needle and within the vertebral body; wherein theultrasound energy delivery device comprises at least one ultrasoundtransducer; and causing the at least one ultrasound transducer todeliver acoustic energy to at least a portion of the vertebral bodysufficient to denervate a target region of the vertebral body comprisinga nociceptive nerve.
 16. The method of claim 15, further comprisingdeflecting a deflectable portion of the ultrasound energy deliverydevice upon insertion.
 17. The method of claim 16, wherein theultrasound energy is delivered from the deflectable portion of theultrasound energy delivery device.
 18. The method of claim 15, furthercomprising passing coolant through a portion of the ultrasound energydelivery device to cool at least one of the portion of the vertebralbody and the ultrasound transducer.
 19. The method of claim 15, furthercomprising: removing the ultrasound energy delivery device from the bodyof the subject; and removing the spinal needle from the body of thesubject.
 20. The method of claim 15, wherein the ultrasound energydelivery device is delivered as a long-term implant.